Il-2-induced cellular events

Critical Reviews in Immunology

Volumn 18, Issue 3, 1997, Pages 185-220

  Gómez, Javier ^a   González, Ana ^a   Martínez A, Carlos ^a   Rebollo, Angelita ^a  

^a UNIVERSIDAD AUTÓNOMA DE MADRID   (Spain)

Author keywords

Apoptosis; Bcl 2; GTP binding proteins; IL 2; IL 2 receptor; Proliferation

Indexed keywords

ACTIN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 2; INTERLEUKIN 2 RECEPTOR; NUCLEAR FACTOR; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN BCL 2; PROTEIN KINASE C; RAS PROTEIN; TRANSCRIPTION FACTOR;

APOPTOSIS; GENE EXPRESSION; GENE TARGETING; HUMAN; NONHUMAN; ONCOGENE; ONCOGENE C FOS; ONCOGENE C JUN; ONCOGENE C MYC; PRIORITY JOURNAL; PROTEIN FAMILY; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; HUMANS; INTERLEUKIN-2; SIGNAL TRANSDUCTION;

EID: 0006897441     PISSN: 10408401     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (444)

1. Smith, K. A., Interleukin-2: inception, impact, and implications, Science, 240, 1169-1176, 1988.
2. Horak, I., Lohler, J., Ma, A., and Smith, K. A., Interleukin-2-deficient mice: a new model to study autoimmunity and self-tolerance, Immunol. Rev., 148, 35-44, 1995.
3. Ma, A., Datta, M., Margosian, E., Chen, J., and Horak, I., T cells, but not B cells, are required for bowel inflammation in interleukin-2-deficient mice, J. Exp. Med., 182, 1567-1572, 1995.
4. Sadlack, B., Lohler, J., Schorle, H., Klebb, G., Haber, H., Sickel, E., Noelle, R. J., and Horak, I., Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells, Eur. J. Immunol., 25, 3053-3059, 1995.
5. +, T cells are responsible for murine interleukin-2-deficient colitis, Eur. J. Immunol., 25, 2618-2625, 1995.
6. Willerford, D. M., Chen, J., Ferry, J. A., Davidson, L., Ma, A., and Alt, F. W., Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment, Immunity, 3, 521-530, 1995.
7. Suzuki, H., Kundig, T. M., Furlonger, C., Wakeham, A., Timms, E., Matsuyama, T., Schmits, R., Simard, J. J., Ohashi, P. S., Griesser, H., Taniguchi, T., Paige, C. J., and Mak, T. W., De-regulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta, Science, 268, 1472-1476, 1995.
8. Kneitz, B., Herrmann, T., Yonehara, S., and Schimpl, A., Normal clonal expansion but impaired Fas-mediated cell death and anergy induction in interleukin-2-deficient mice, Eur. J. Immunol., 25, 2572-2577, 1995.
9. Taniguchi, T., Matsui, H., Fujito, T., Takaoka, C., Kashima, ?., Yushimoto, R., and Hamuro, J., Structure and expression of a cloned cDNA for human IL-2, Nature, 302, 305-310, 1983.
10. Robb, R. J., Kutny, R. M., Panico, M., Morris, H. R., and Chowdhry, V., Amino acid sequence and posttranslational modification of human interleukin-2, Proc. Natl. Acad. Sci. U.S.A., 81, 6486-6490, 1984.
11. Wang, A., Lu, S. D., and Mark, D. F., Site specific mutagenesis of the human interleukin-2 gene: structure-function analysis of the cysteine residues, Science, 224, 1431-1433, 1984.
12. Kashima, N., Nishi-Takaoka, C., Fujita, T., Taki, S., Yamada, G., Hanuro, J., and Taniguchi, T., Unique structure of murine interleukin-2 as deduced from cloned cDNAs, Nature, 313, 402-404, 1985.
13. Holbrook, N. J., Smith, K. A., Fornace, A. J., Jr., Comeau, C. M., Wiskocil, R. L., and Crabtree, G. R., T-cell growth factor: complete nucleotide sequence and organization of the gene in normal and malignant cells, Proc. Natl. Acad. Sci. U.S.A., 81, 1634-1638, 1984.
14. Seigel, L. J., Harper, M. E., Wong-Staal, F., Gallo, R. C., Nash, W. G., and O'Brien, S. J., Gene for T-cell growth factor: location on human chromosome 4q and feline chromosome B1, Science, 223, 175-178, 1984.
15. Wang, H. M. and Smith, K. A., The interleukin-2-receptor. Functional consequences of its bimolecular structure, J. Exp. Med., 166, 1055-1069, 1987.
16. Hatakeyama, M., Mori, H., Doi, T., and Taniguchi, T., A restricted cytoplasmic region of IL-2 receptor beta chain is essential for growth signal transduction but not for ligand binding and internalization, Cell, 59, 837-845, 1989a.
17. Nakamura, Y., Russell, S. M., Mess, S. A., Friedmann, M., Erdos, M., Francois, C., Jacques, Y., Adelstein, S., and Leonard, W. J., Heterodimerization of the IL-2 receptor beta- and gamma-chain cytoplasmic domains is required for signaling, Nature, 369, 330-333, 1994.
18. Nelson, B. H., Lord, J. D., and Greenberg, P. D., Cytoplamic domains of the interleukin-2 receptor beta and gamma chains mediate the signal for T-cell proliferation, Nature, 369, 333-336, 1994.
19. Hatakayama, M., Transmembrane signaling of interleukin 2 receptor. Conformation and function of human interleukin 2 receptor (p55)/insulin receptor chimeric molecules, J. Exp. Med., 166, 362-375, 1987.
20. Rubin, L. A., Kurman, C. C., Fritz, M. E., Biddison, W. E., Boutin, B., Yarchoan, R., and Nelson D. L., Soluble interleukin 2 receptors are released from activated human lymphoid cells in vitro, J. Immunol., 135, 3172-3177, 1985.
21. Osawa, H., Josimovic-Alasevic, O., and Diamantstein, T., Interleukin 2 receptors are released by cells in vitro and in vivo. Detection of soluble IL-2 receptors in cell culture suprenatants and in the serum of mice by an immunoradiometric assay, Eur. J. Immunol., 16, 467-469, 1986.
22. Ascherman, D. P., Migone, T. S., Friedman, M. C., and Leonard, W. J., Interleukin-2 (IL-2)-mediated induction of the IL-2 receptor alpha chain gene. Critical role of two functionally redundant tyrosine residues in the IL-2 receptor beta chain cytoplasmic domain and suggestions that these residues mediate more than Stat5 activation, J. Biol. Chem., 272, 8704-8709, 1997.
23. Liu, K. D., Greene, W. C., and Goldsmith, M. A., The alpha chain of the IL-2 receptor determines the species specificity of high-affinity IL-2 binding, Cytokine, 8, 613-621, 1996.
24. Kuziel, W. A., Ju, G., Grdina, T. A., and Greene, W. C., Unexpected effects of the IL-2Rα subunit on high-affinity IL-2R assembly and function detected with a mutant IL-2 analog, J. Immunol., 150, 3357-3365, 1993.
25. Greene, W. C. and Leonard, W. J., The human interleukin-2 receptor, Annu. Rev. Immunol., 4, 69-74, 1986.
26. Cantrell, D. A. and Smith, K. A., Transient expression of interleukin-2 receptors. Consequences for T cell growth, J. Exp. Med., 158, 1895-1911, 1983.
27. Ascherman, D. P., Migone, T. S., Friedman, M. C., and Leonard, W. J., Interleukin-2 (IL-2)-mediated induction of the IL-2 receptor α chain gene, J. Biol. Chem., 272, 8704-8709, 1997.
28. Leonard, W. J., Donlon, T. A., Levo, R. V., and Greene, W. C., Localization of the gene encoding the human interleukin-2 receptor on chromosome 10, Science, 228, 1547-1549, 1985.
29. Sperisen, P., Wang, S. M., Soldaini, E., Pla, M., Rusterholz, C., Bucher, P., Corthesy, P., Reichenbach, P., and Naboholz, M., IL-2 and IL-2 control transcription via distinct cis-acting elements, J. Biol. Chem., 270, 10743-10753, 1995.
30. Soldaini, E., Pla, M., Bermann, F., Espel, E., Corthesi, P., Borange, S., Waanders, G. A., McDonald, H. R., and Nabohlz, M., Mouse IL-2Rα gene expression: delimitation of cis-acting regulatory elements in transgenic mice and by mapping of DNAse hipersensitive sites, J. Biol. Chem., 270, 10733-10742, 1995.
31. John, S., Reeves, R. B., Lin, J., Child, R., Leiden, J. M., Thompson, C. B., and Leonard, W. S., Regulation of cell type-specific IL-2Rα chain gene expression: potential role of physical interactions between Elf-1, HMG-I(Y) and NF-κB family proteins, Mol. Cell. Biol., 15, 1786-1776, 1995.
32. John, S., Robbins, C. M., and Leonard, W. J., An IL-2 response element in human IL-2 receptor alpha chain promoter is a composite element that binds Stat5, Elf-1, HMG-I(Y) and GATA family protein, EMBO J., 15, 5627-5635, 1996.
33. Pitton, C., Rebollo, A., Van Snick, J., Theze, J., and Garcia, A., High-affinity and intermediate-affinity forms of the human IL-2R expressed in an IL-9-dependent murine T cell line delivers proliferation signal via differences in their transduction pathways, Cytokine, 5, 362-371, 1993.
34. Merida, I., Williamson, P., Kuziel, W. A., Green, W. A., and Gaulton, G. N., The serine-rich cytoplasmic domain of the IL-2Rβ chain is essential for IL-2-dependent tyrosine protein kinase and PI3 kinase, J. Biol. Chem., 268, 6765-6779, 1993.
35. Tagaya, Y., Bauford R. N., De Filippis, A. P., and Waldman, T. A., IL-15: a pleiotropic cytokine with diverse receptor signaling pathways whose expression is controlled at multiple levels, Immunity, 4, 329-336, 1996.
36. Cosman, D., Lyman, S. D., Idzerda, R. L., Beckman, M. P., Park, L. S., Goodwill, R. G., and March, C. J., A new cytokine receptor superfamily, Trends. Biochem. Sci., 15, 265-270, 1990.
37. Gnarra, J. R., Otani, H., Wang, M. G., McBride, O. W., Sharon, M., and Leonard, W. J., Human interleukin 2 receptor beta-chain gene: chromosomal localization and identification of 5′ regulatory sequences, Proc. Natl. Acad. Sci. U.S.A., 87, 3440-3444, 1990.
38. Lin, J. X., Bhat, N. K., John, S., Queale, W. S., and Leonard, W. J., Characterization of the human interleukin-2 receptor beta-chain gene promoter: regulation of promoter activity by ets gene products, Mol. Cell. Biol., 13, 6201-6210, 1993.
39. Roessler, E., Grant, A., Ju, G., Tsudo, M., Sugamura, K., and Waldmann, T. A., Cooperative interactions between the interleukin 2 receptor alpha and beta chains alter the interleukin 2-binding affinity of the receptor subunits, Proc. Natl. Acad. Sci. U.S.A., 91, 3344-3347, 1994.
40. Goldsmith, M. A., Amaral, M. C., and Greene, W. C., Ligand binding by the IL-2 receptor is modulated by intracellular determinants of the IL-2 receptor beta-chain, J. Immunol., 154, 2033-2040, 1995.
41. Shibuya, H., Yoneyama, M., Ninomiya-Tsuji, J., Matsumoto, K., and Taniguchi, T., IL-2 and TGF receptors stimulate the hematopoietic cell cycle via different signaling pathways: demonstration of a novel role for c-myc, Cell, 70, 57-64, 1992.
42. Kishimoto, T., Taga, T., and Akira, S., Cytokine signal transduction, Cell, 76, 253-262, 1994.
43. Goldsmith, M. A., Lai, S. Y., Xu, W., Amaral, M. C., Kuczek, E. S., Parent, L. J., Mills, G. B., Tarr, K. L., Longmore, G. D., and Greene, W. C., Growth signal transduction by the human interleukin-2 receptor requires cytoplasmic tyrosines of the beta chain and nontyrosine residues of the gamma c chain, J. Biol. Chem., 270, 21729-21737, 1995.
44. Leonard, W. J., Noguchi, M., and Russell, S. M., Sharing of a common gamma chain, gamma c, by the IL-2, IL-4, and IL-7 receptors: implications for X-linked severe combined immunodeficiency (XSCID), Adv. Exp. Med. Biol., 365, 225-232, 1994.
45. Boesteanu, A., Silva, A. D. D., Nakajima, H., Leonard, W. J., Peschon, J. J., and Joyce, S., Distinct roles for signals relayed through the common cytokine receptor gamma chain and interleukin 7 receptor alpha chain in natural T cell development, J. Exp. Med., 186, 331-336, 1997.
46. Arima, N., Kamio, M., Imada, K., Hori, T., Hattori, T., Tsudo, M., Okuma, M., and Uchiyama, T., Pseudo-high-affinity interleukin-2 (IL-2) receptor lacks the third component that is essential for functional IL-2 binding and signaling, J. Exp. Med., 176, 1265-1272, 1992.
47. Zurawski, S. M., Imler, J. L., and Zurawski, G., Partial agonist/antagonist mouse interleukin-2 proteins indicate that a third component of the receptor complex functions in signal transduction, EMBO J., 9, 3899-3905, 1990.
48. Kawahara, A., Minami, Y., and Taniguchi, T., Evidence for a critical role for the cytoplasmic region of the interleukin 2 (IL-2) receptor gamma chain in IL-2, IL-4, and IL-7 signaling, Mol. Cell. Biol., 14, 5433-5440, 1994.
49. Leonard, W. J., Dysfunctional cytokine receptor signaling in severe combined immunodeficiency, J. Invest. Med., 44, 304-311, 1996.
50. Leonard, W. J., The defective gene in X-linked severe combined immunodeficiency encodes a shared interleukin receptor subunit: implications for cytokine pleiotropy and redundancy, Curr. Opin. Immunol., 6, 631-635, 1994.
51. Leonard, W. J., The molecular basis of X-linked severe combined immunodeficiency: defective cytokine receptor signaling, Annu. Rev. Med., 47, 229-239, 1996.
52. Schmalstieg, F. C., Leonard, W. J., Noguchi, M., Berg, M., Rudloff, H. E., Denney, R. M., Dave, S. K., Brooks, E. G., and Goldman, A. S., Missense mutation in exon 7 of the common gamma chain gene causes a moderate form of X-linked combined immunodeficiency, J. Clin. Invest., 95, 1169-1173, 1995.
53. Nakajima, H., Shores, E., Noguchi, M., and Leonard, W. J., The common cytokine receptor γ chain plays an essential role in regulating lymphoid homeostasis, J. Exp. Med., 185, 189-196, 1997.
54. He, Y. W., Nakajima, H., Leonard, W. J., Adkins, B., and Malek, T. R., The common gamma chain of cytokine receptors regulates intrathymic T cell development at multiple stages, J. Immunol., 158, 2592-2599, 1997.
55. Cao, X., Kozak, C. A., Liu, Y. J., Noguchi, M., O'Connell, E., and Leonard, W. J., Characterization of cDNAs encoding the murine interleukin 2 receptor (IL-2R) gamma chain: chromosomal mapping and tissue specificity of IL-2R gamma chain expression, Proc. Natl. Acad. Sci. U.S.A., 90, 8464-8468, 1993.
56. Miyazaki, T., Kawahara, A., Fujui, H., Nakawaga, Y., Minai, Y., Liu, Z.J., Oishi, I., Silvennoineu, O., Witthuhn, B. A., Ihle, J. A., and Taniguchi, T., Functional activation of JAK1 and JAK3 by selective association with IL-2 receptor subunits, Science, 266, 1045-1047, 1994.
57. c chain sufficient for Jak kinase activation and induction of proliferation in T cells, Mol. Cell. Biol., 16, 309-317, 1996.
58. Fujitani, Y., Hibi, M., Fukada, T., Takahashi-Tezuka, M., Yoshida, H., Yamaguchi, T., Sugiyama, K., Yamanaka, Y., Nakajima, K., and Hirano, T., An alternative pathway for STAT activation that is mediated by the direct interaction between JAK and STAT, Oncogene, 14, 751-761, 1997.
59. Higuchi, M., Asao, H., Tanaka, N., Oda, K., Takeshita, T., and Sugamura, K., Regulation of IL-2 signaling, Leukemia, 11(Suppl. 3), 416-417, 1997.
60. Yin, T., Shen, R., Feng, G-S., and Yang, Y-C., Molecular characterization of specific interactions between SHP-2 phosphatase and JAK tyrosine kinases, J. Biol. Chem., 272, 1032-1037, 1997.
61. Haque, S. J., Wu, Q., Kammer, W., Friedrich, K., Smith, J. M., Kerr, I. M., Stark, G. R., and Williams, B. R. G., Receptor-associated constitutive protein tyrosine phosphatase activity controls the kinase function of JAK1, Proc. Natl. Acad. Sci. U.S.A., 94, 8563-8568, 1997.
62. Horvath, C. M., Wen, Z., and Darnell, J. E. J., A STAT protein that determines DNA sequence recognition suggests a novel DNA-binding domain, Genes Dev., 9, 984-994, 1995.
63. Stahl, N., Farruggella, T. J., Boulton, T. G., Zhong, Z., Darnell, J. E., and Yankopoulus, G. D., Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptor, Science, 267, 1349-1353, 1995.
64. Kirken, R. A., Malabarba, M. G., Xu, J., DaSilva, L., Erwin, R. A., Liu, X., Hennighausen, L., Rui, H., and Farrar, W. L., Two discrete regions of interleukin-2 (IL-2) receptor β independently mediate IL-2 activation of a PD98059/Rapamycin/Wortmannin-insensitive Stat5a/b serine kinase, J. Biol. Chem., 272, 15459-15465, 1997.
65. Lin, J. X., Mietz, J., Modi, W. S., John, S., and Leonard, W. J., Cloning of human Stat 5B. Reconstitution of interleukin-2-induced Stat5A and Stat5B DNA binding activity in COS-7 cells, J. Biol. Chem., 271, 19738-10744, 1996.
66. Kawahara, A., Minami, Y., Miyazaki, T., Ihle, J. N., and Taniguchi, T., Critical role of the interleukin 2 (IL-2) receptor gamma-chain-associated Jak3 in the IL-2-induced c-fos and c-myc, but not bcl-2, gene induction, Proc. Natl. Acad. Sci. U.S.A., 92, 8724-8728, 1995.
67. Takeshita, T., Arita, T., Asao, H., Tanaka, N., Higuchi, M., Kuroda, H., Kaneko, K., Munakata, H., Endo, Y., Fujita, T., and Sugamura, K., Cloning of a novel signal-transducing adaptor molecule containing an SH3 domain and ITAM, Biochem. Biophys. Res. Commun., 225, 1035-1039, 1996.
68. Takeshita, T., Arita, T., Higuchi, M., Asao, H., Endo, K., Kuroda, H., Tanaka, N., Murata, K., Ishii, N., and Sugamura, K., STAM, signal transducing adaptor molecule, is associated with Janus kinases and involved in signaling for cell grwth and c-myc induction, Immunity, 6, 449-457, 1997.
69. lck, EMBO J., 12, 759-768, 1993.
70. Hatakeyama, M., Kawahara, A., Mori, H., Shibuya, H., and Taniguchi, T., C-fos gene induction by interleukin 2: identification of the critical cytoplasmic regions within the interleukin 2 receptor beta chain, Proc. Natl. Acad. Sci. U.S.A., 89, 2022-2028, 1992.
71. Gulbins, E., Bissonnette, R., Mahboubi, A., Martin, S., Nishioka, W., Brunner, T., Baier, G., Baier-Bitterlich, G., Byrd, C., and Lang, F., FAS-induced apoptosis is mediated via a ceramide-initiated Ras signaling pathway, Immunity, 2, 341-351, 1995.
72. Minami, Y., Nakagawa, Y., Kawahara, A., Miyazaki, T., Sada, K., Yamamura, H., and Taniguchi, T., Protein tyrosine kinase Syk is associated with and activated by the IL-2 receptor: possible link with the c-myc induction pathway, Immunity, 2, 89-100, 1995.
73. Couture, C., Baier, G., Oetken, C., Willians, S., Telford, D., Cardine, A. M., Fischer, S., Burn, P., Altman, A., and Mustelin, T., Activation of p56lck by p72syk through physical association and N-terminal tyrosine phosphorylation, Mol. Cell. Biol., 14, 5249-5258, 1994.
74. Mustelin, T. and Burn, P., Regulation of srk family tyrosine kinases in lymphocytes, Trends. Biochem. Sci., 18, 215-220, 1993.
75. Lee, J. M., Fournel, M., Veillette, A., and Branton, P. A., Association of CD45 with Lck and components of the Ras signaling pathway in pervanadate-treated mouse T-cell lines, Oncogene, 18, 253-263, 1996.
76. Hall, A., Ras-related proteins, Curr. Opin. Cell. Biol., 5, 265-268, 1993.
77. Jimenez, B., Arends, M., Esteve, P., Perona, R., Sanchez, R., Ramon y Cajal, S., Wyllie, A., and Lacal, J. C., Induction of apoptosis in NIH3T3 cells after serum deprivation by overexpression of rho-p21, a GTPase protein of the ras superfamily, Oncogene, 10, 811-816, 1995.
78. Denhardt, D. T., Signal-transducing protein phosphorylation cascades mediated by Ras/Rho proteins in the mammalian cell: the potential for multiplex signalling, Biochem. J., 318, 729-747, 1996.
79. Tapon, N. and Hall, A., Rho, Rac and Cdc42 GTPases regulate the organization of the actin cytoskeleton, Curr. Opin. Cell. Biol., 9, 86-92, 1997.
80. Gomez, J., Martínez-A, C., Fernandez, B., Garcia, A., and Rebollo, A., Critical role of Ras in the proliferation and prevention of apoptosis mediated by IL-2, J. Immunol., 157, 2272-2281, 1996.
81. McCormick, F., Ras signaling and NF1, Curr. Opin. Genet. Dev., 5, 51-55, 1995a.
82. Glomset, J. A. and Farnsworth, C. C., Role of protein modification reactions in programming interactions between ras-related GTPases and cell membranes, Annu. Rev. Cell. Biol. 10, 181-205, 1994.
83. Graham, S. M., Vojtek, A. B., Huff, S. Y., Cox, A. D., Clark, G. J., and Cooper, J. A., Der-CJ TC21 causes transformation by Raf-independent signaling pathways, Mol. Cell. Biol., 16, 6132-6140, 1996.
84. Wittinghofer, A. and Herrmann, C., Ras-effector interactions, the problem of specificity, FEBS Lett., 369, 52-56, 1995.
85. Wittinghofer, A. and Nassar, N., How Ras-related proteins talk to their effectors, Trends. Biochem. Sci., 21, 488-491, 1996.
86. Del Villar, K., Dorin, D., Sattler, I., Urano, J., Poullet, P., Robinson, N., Mitsuzawa, H., and Tamanoi, F., C-terminal motifs found in Ras-super-family G-proteins: CAAX and C-seven motifs, Biochem. Soc. Trans., 24, 709-713, 1996.
87. Zhang, F. L. and Casey, P. J., Protein prenylation: molecular mechanisms and functional consequences, Annu. Rev. Biochem., 65, 241-269, 1996.
88. Hart, K. C. and Donoghue, D. J., Derivatives of activated H-ras lacking C-terminal lipid modifications retain transforming ability if targeted to the correct subcellular location, Oncogene, 14, 945-953, 1997.
89. Leevers, S. J., Paterson, H. F., and Marshall, C. J., Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane, Nature, 369, 411-414, 1994.
90. Bernards, A., Neurofibromatosis type 1 and Ras- mediated signaling: filling in the GAPs, Biochim. Biophys. Acta., 1242, 43-59, 1995.
91. Bowtell, D., Fu, P., Simon, M., and Senior, P., Identification of murine homologues of the Drosophila son of sevenless gene: potential activators of ras, Proc. Natl. Acad. Sci. U.S.A., 89, 6511-6515, 1992.
92. Liu, B. X., Wei, W., and Broek, D., The catalytic domain of the mouse sos1 gene, Eur. J. Immunol., 21, 1905-1911, 1991.
93. Quilliam, L. A., Khosravi Far, R., Huff, S. Y., and Der, C. J., Guanine nucleotideexchange factors: acti- vators of the Ras superfamily of proteins, Bioessays, 17, 395-404, 1995.
94. Overbeck, A. F., Brtva, T. R., Cox, A. D., Graham, S. M., Huff, S. Y., Khosravi Far, R., Quilliam, L. A., Solski, P. A., and Der, C. J., Guanine nucleotide exchange factors: activators of Ras superfamily proteins, Mol. Reprod. Dev., 42, 468-476, 1995.
95. Koch, C. A., Anderson, D., Moran, M. F., Ellis, C., and Pawson, T., SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins, Science, 252, 668-674, 1991.
96. Ren, R., Mayer, B. J., Cicchetti, P., and Baltimore, D., Identification of a ten-amino acid proline-rich SH3 binding site, Science, 259, 1157-1161, 1993.
97. Wandless, T. J., SH2 domains: a question of independence, Curr. Biol., 6, 125-127, 1996.
98. Birge, R. B., Knudsen, B. S., Besser, D., and Hanafusa, H., SH2 and SH3-containing adaptor proteins: redundant or independent mediators of intracellular signal transduction, Genes Cells, 1, 595-613, 1996.
99. Pelicci, G., Lanfrancone, L., Grignani, F., McGlade, J., Cavallo, F., Forni, G., Nicoletti, I., Grignani, F., Pawson, T., and Pelicci, P. G., A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction, Cell, 70, 93-104, 1992.
100. Rozakis-Adcock, M., McGlade, J., Mbamalu, G., Pelicci, G., Daly, R., Li, W., Batzer, A., Thomas, S., Brugge, J., Pelicci, P. G., Schlessinger, J., and Pawson, T., Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases, Nature, 360, 689-692, 1992.
101. Lowenstein, E. J., Daly, R. J., Batzer, A. G., Li, W., Margolis, B., Lammers, R., Ullrich, A., Skolnik, E. Y., Bar, S. D., and Schlessinger, J., The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling, Cell, 70, 431-442, 1992.
102. Li, N., Batzer, A., Daly, R., Yajnik, V., Skolnik, E., Chardin, P., Bar Sagi, D., Margolis, B., and Schlessinger, J., Guanine-nucleotide-releasing factor hSos1 binds toGrb2 and links receptor tyrosine kinases to Ras signaling, Nature, 363, 85-88, 1993.
103. Rozakis-Adcock, M., Fernley, R., Wade, J., Pawson, T., and Bowtell, D., The SH2 and SH3 domains of mammalian Grb2 couple the EGF receptor to the Ras activator mSos1, Nature, 363, 83-85, 1993.
104. Simon, M. A., Dodson, G. S., and Rubin, G. M., An SH3-SH2-SH3 protein is required for p21Ras1 activation and binds to sevenless and Sos proteins in vitro, Cell, 73, 169-177, 1993.
105. Izquierdo, M., Downward, J., Graves, J. D., and Cantrell, D. A., Role of protein kinase C in T-cell antigen receptor regulation of p21ras: evidence that two p21ras regulatory pathways coexist in T cells, Mol. Cell. Biol., 12, 3305-3312, 1992a.
106. Buday, L., Egan, S. E., Rodriguez, V. P., Cantrell, D. A., and Downward, J., A complex of Grb2 adaptor protein, Sos exchange factor, and a 36-kDa membrane-bound tyrosine phosphoprotein is implicated in ras activation in T cells, J. Biol. Chem., 269, 9019-9023, 1994.
107. Feng, G. S., Ouyang, Y. B., Hu, D. P., Shi, Z. Q., Gentz, R., and Ni, J., Grap is a novel SH3-SH2-SH3 adaptor protein that couples tyrosine kinases to the Ras pathway, J. Biol. Chem., 271, 12129-12132, 1996.
108. Trub, T., Frantz, J. D., Miyazaki, M., Band, H., and Shoelson, S. E., The role of a lymphoid-restricted, Grb2-like SH3-SH2-SH3 protein in T cell receptor signaling, J. Biol. Chem., 272, 894-902, 1997.
109. Katz, M. E. and McCormick, F., Signal transduction from multiple Ras effectors, Curr. Opin. Immunol., 4, 71-79, 1994.
110. Marshall, C. J., Ras effectors, Curr. Opin. Cell. Biol., 8, 197-204, 1996.
111. McCormick, F. and Wittinghofer, A., Interactions between Ras proteins and their effectors, Curr. Opin. Biotech., 7, 449-456, 1996.
112. Marshall, M., Interactions between Ras and Raf: key regulatory proteins in cellular transformation, Mol. Reprod. Dev., 42, 493-499, 1995.
113. Rodriguez-Viciana, P., Marte, B. M., Warne, P. H., and Downward, J., Phosphatidylinositol 3′ kinase: one of the effectors of Ras, Philos. Trans. R. Soc. Lond. B. Biol. Sci., 351, 225-231, 1996.
114. Berra, E., Diaz-Meco, M. T., Lozano, J., Frutos, S., Municio, M. M., Sanchez, P., Sanz, L., and Moscat, J., Evidence for a role of MEK and MAPK during signal transduction by protein kinase C zeta, EMBO J., 14, 6157-6163, 1995.
115. Ikeda, M., Koyama, S., Okazaki, M., Dohi, K., and Kikuchi, A., Rap1 p21 regulates the interaction of ras p21 with RGL, a new effector protein of ras p21, FEBS Lett., 375, 37-40, 1995.
116. White, M. A., Vale, T., Camonis, J. H., Schaefer, E., and Wigler, M. H., A role for the Ra1 guanine nucleotide dissociation stimulator in mediating Ras-induced transformation, J. Biol. Chem., 271, 16439-16442, 1996.
117. Russell, M., Lange-Carter, C. A., and Johnson, G. L., Direct interaction between Ras and the kinase domain of mitogen-activated protein kinase kinase kinase (MEKK1), J. Biol. Chem., 270, 11757-11760, 1995.
118. Zhang, Y., Yao, B., Delikat, S., Bayoumy, S., Lin, X. H., Basu, S., McGinley, ?., Chan-Hui, P. Y., Lichenstein, H., and Kolesnick, R., Kinase suppressor of Ras is ceramide-activated protein kinase, Cell, 89, 63-72, 1997.
119. Han, L., Wong, D., Dhaka, A., Afar, D., White, M., Xie, W., Herschman, H., Witte, O., and Colicelli, J., Protein binding and signaling properties of RIN1 suggest a unique effector function, Proc. Natl. Acad. Sci. U.S.A., 94, 4954-4959, 1997.
120. Cales, C., Hancock, J. F., Marshall, C. J., and Hall, A., The cytoplasmic protein GAP is implicated as the target for regulation by the ras gene product, Nature, 332, 548-551, 1988.
121. Tocque, B., Delumeau, I., Parker, F., Maurier, F., Multon, M. C., and Schweighoffer, F., Ras-GTPase activating protein (GAP): a putative effector for Ras, Cell. Signal., 9, 153-158, 1997.
122. Parker, F., Maurier, F., Delumeau, I., Duchesne, M., Faucher, D., Debussche, L., Dugue, A., Schweighoffer, F., and Tocque, B., A Ras-GTPaseactivating protein SH3-domain-binding protein, Mol. Cell. Biol., 16, 2561-2569, 1996.
123. Vojtek, A. B., Hollenberg, S. M., and Cooper, J. A., Mammalian Ras interacts directly with the serine/threonine kinase Raf, Cell, 74, 205-214, 1993.
124. Warne, P. H., Viciana, P. R., and Downward, J., Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro, Nature, 364, 352-355, 1993.
125. Morrison, D. K. and Cutler, R. E., The complexity of Raf-1 regulation, Curr. Opin. Cell. Biol., 9, 174-179, 1997.
126. Leevers, S. J., Paterson, H. F., and Marshall, C. J., Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane, Nature, 369, 411-414, 1994.
127. Stokoe, D., Macdonald, S. G., Cadwallader, K., Symons, M., and Hancock, J. F., Activation of Raf as a result of recruitment to the plasma membrane, Science, 264, 1463-1467, 1994.
128. Jelinek, T., Dent, P., Sturgill, T. W., and Weber, M. J., Ras-induced activation of Raf-1 is dependent on tyrosine phosphorylation, Mol. Cell. Biol., 16, 1027-1034, 1996.
129. Wartmann, M. and Davis, R. J., The native structure of the activated Raf protein kinase is a membrane-bound multi-subunit complex, J. Biol. Chem., 269, 6695-6701, 1994.
130. Schulte, T. W., Blagosklonny, M. V., Ingui, C., and Neckers, L., Disruption of the Raf-l-Hsp90 molecular complex results in destabilization of Raf-1 and loss of Raf-1-Ras association, J. Biol. Chem., 270, 24585-24588, 1995.
131. Li, S., Janosch, P., Tanji, M., Rosenfeld, G. C., Waymire, J. C., Mischak, H., Kolch, W., and Sedivy, J. M., Regulation of Raf-1 kinase activity by the 14-3-3 family of proteins, EMBO J., 14, 685-696, 1995.
132. Rommel, C., Radziwill, G., Lovric, J., Noeldeke, J., Heinicke, T., Jones, D., Aitken, A., and Moeling, K., Activated Ras displaces 14-3-3 protein from the amino terminus of c-Raf-1, Oncogene, 12, 609-619, 1996.
133. Xing, H., Kornfeld, K., and Muslin, A. J., The protein kinase KSR interacts with 14-3-3 protein and Raf, Curr. Biol., 7, 294-300, 1997.
134. Luo, Z., Tzivion, G., Belshaw, P. J., Vavvas, D., Marshall, M., and Avruch, J., Oligomerization activates c-Raf-1 through a Ras-dependent mechanism, Nature, 383, 181-185, 1996.
135. Conklin, D. S., Galaktionov, K., and Beach, D., 14-3-3 proteins associate with cdc25 phosphatases, Proc. Natl. Acad. Sci. U.S.A., 92, 7892-7896, 1995.
136. Su, B. and Karin, M., Mitogen-activated protein kinase cascades and regulation of gene expression, Curr. Opin. Immunol., 8, 402-411, 1996.
137. Marais, R. and Marshall, C. J., Control of the ERK MAP kinase cascade by Ras and Raf, Cancer Surv., 27, 101-125, 1996.
138. Robinson, M. J. and Cobb, M. H., Mitogen-activated protein kinase pathways, Curr. Opin. Cell. Biol., 9, 180-186, 1997.
139. Galaktionov, K., Jessus, C., and Beach, D., Raf1 interaction with Cdc25 phosphatase ties mitogenic signal transduction to cell cycle activation, Genes Dev., 9, 1046-1058, 1995.
140. Fisher, R. P., CDKs and cyclins in transition(s), Curr. Opin. Genet. Dev., 7, 32-38, 1997.
141. Papin, C., Denouel, A., Calothy, G., and Eychene, A., Identification of signalling proteins interacting with B-Raf in the yeast two-hybrid system, Oncogene, 12, 2213-2221, 1996.
142. Downward, J., Cell cycle: routine role for Ras, Curr. Biol., 7, R258-R260, 1997.
143. Treisman, R., Regulation of transcription by MAP kinase cascades, Curr. Opin. Cell. Biol., 8, 205-215, 1996.
144. Downward, J., Graves, J. D., Warne, P. H., Rayter, S., and Cantrell, D. A., Stimulation of p21ras upon T-cell activation, Nature, 346, 719-723, 1990.
145. Izquierdo Pastor, M., Reif, K., and Cantrell, D., The regulation and function of p21ras during T-cell activation and growth, Immunol. Today, 16, 159-164, 1995.
146. Rayter, S. I., Woodrow, M., Lucas, S. C., Cantrell, D. A., and Downward, J., p21ras mediates control of IL-2 gene promoter function in T cell activation, EMBO J., 11, 4549-4556, 1992.
147. Jain, J., Loh, C., and Rao, A., Transcriptional regulation of the IL-2 gene, Curr. Opin. Immunol., 7, 333-342, 1995.
148. Satoh, T., Nakafuku, M., Miyajima, A., and Kaziro, Y., Involvement of ras p21 protein in signal-transduction pathways from interleukin 2, interleukin 3, and granulocyte/macrophage colony-stimulating factor, but not from interleukin 4, Proc. Natl. Acad. Sci. U.S.A., 88, 3314-3318, 1991.
149. Graves, J. D., Downward, J., Izquierdo, P. M., Rayter, S., Warne, P. H., and Cantrell, D. A., The growth factor IL-2 activates p21ras proteins in normal human lymphocytes, J. Immunol., 148, 2417-2422, 1992.
150. Izquierdo, M., Downward, J., Otani, H., Leonard, W. J., and Cantrell, D. A., Interleukin (IL)-2 activation of p21ras in murine myeloid cells transfected with human IL-2 receptor beta chain, Eur. J. Immunol., 22, 817-821, 1992b.
151. Izquierdo, M. and Cantrell, D. A., Protein tyrosine kinases couple the interleukin-2 receptor to p21ras, Eur. J. Immunol., 23, 131-135, 1993.
152. Burns, L. A., Karnitz, L. M., Sutor, S. L., and Abraham, R. T., Interleukin-2-induced tyrosine phosphorylation of p52shc in T lymphocytes, J. Biol. Chem., 268, 17659-17661, 1993.
153. Ravichandran, K. S. and Burakoff, S. J., The adapter protein Shc interacts with the interleukin-2 (IL-2) receptor on IL-2 stimulation, J. Biol. Chem., 269, 1599-1602, 1994.
154. Turner, B., Rapp, U., App, H., Greene, M., Dobashi, K., and Reed, J., Interleukin 2 induces tyrosine phosphorylation and activation of p72-74 Raf-1 kinase in a T-cell line, Proc. Natl. Acad. Sci. U.S.A., 88, 1227-1231, 1991.
155. Zmuidzinas, A., Mamon, H. J., Roberts, T. M., and Smith, K. A., Interleukin-2-triggered Raf-1 expression, phosphorylation, and associated kinase activity increase through G1 and S in CD3-stimulated primary human T cells, Mol. Cell. Biol., 11, 2794-2803, 1991.
156. Maslinski, W., Remillard, B., Tsudo, M., and Strom, T. B., Interleukin-2 (IL-2) induces tyrosine kinase-dependent translocation of active raf-1 from the IL-2 receptor into the cytosol, J. Biol. Chem., 267, 15281-15284, 1992.
157. Turner, B. C., Tonks, N. K., Rapp, U. R., and Reed, J. C., Interleukin 2 regulates Raf-1 kinase activity through a tyrosine phosphorylation-dependent mechanism in a T-cell line, Proc. Natl. Acad. Sci. U.S.A., 90, 5544-5548, 1993.
158. Riedel, D., Brennscheidt, U., Kiehntopf, M., Brach, M., and Herrmann, F., The mitogenic response of T cells to interleukin-2 requires Raf-1, Eur. J. Immunol., 23, 3146-3150, 1993.
159. Watts, J. D., Welham, M. J., Kalt, L., Schrader, J. W., and Aebersold, R., IL-2 stimulation of T lymphocytes induces sequential activation of mitogen-activated protein kinases and phosphorylation of p56lck at serine-59, J. Immunol., 151, 6862-6871, 1993.
160. Perkins, G. R., Marvel, J., and Collins, M. K., Interleukin 2 activates extracellular signal-regulated protein kinase 2, J. Exp. Med., 178, 1429-1434, 1993.
161. Minami, Y., Oishi, I., Liu, Z. J., Nakagawa, S., Miyazaki, T., and Taniguchi, T., Signal transduction mediated by the reconstituted IL-2 receptor. Evidence for a cell type-specific function of IL-2 receptor beta-chain, J. Immunol., 152, 5680-5690, 1994.
162. Taieb, J., Blanchard, D. A., Auffredou, M. T., Chaouchi, N., and Vazquez, A., In vivo association between p56lck and MAP kinase during IL-2-mediated lymphocyte proliferation, J. Immunol., 155, 5623-5630, 1995.
163. Gómez, J., Martínez-A, C., Giry, M., García, A., and Rebollo, A., Rho prevents apoptosis through Bcl-2 expression: implications for IL-2 receptor signal, Eur. J. Immunol., 27, in press, 1997.
164. Kelly, K. and Siebenlist, U., Immediate-early genes induced by antigen receptor stimulation, Curr. Opin. Immunol., 7, 327-332, 1995.
165. Grumont, R. J., Rasko, J. E., Strasser, A., and Gerondakis, S., Activation of the mitogen-activated protein kinase pathway induces transcription of the PAC-1 phosphatase gene, Mol. Cell. Biol., 16, 2913-2921, 1996.
166. Miyazaki, T., Liu, Z., Kawahara, A., Minami, Y., Minami, K., Yamada, K., Tsujimoto, Y., Barsoumain, E. L., Perlmutter, R. L., and Taniguchi, T., Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation, Cell, 81, 223-231, 1995.
167. Satoh, T., Minami, Y., Kono, T., Yamada, K., Kawahara, A., Taniguchi, T., and Kaziro, Y., Interleukin 2-induced activation of Ras requires two domains of interleukin 2 receptor beta subunit, the essential region for growth stimulation and Lck-binding domain, J. Biol. Chem., 267, 25423-25427, 1992.
168. de Vries, J. E., ten-Kate, J., and Busman, F. T., p21ras in carcinogenesis, Pathol. Res. Pract., 192, 658-668, 1996.
169. Abrams, S. I., Hand, P. H., Tsang, K. Y., and Schlom, J., Mutant ras epitopes as targets for cancer vaccines, Semin. Oncol., 23, 118-134, 1996.
170. Filmus, J., Robles, A. I., Shi, W., Wong, M. J., Colombo, L. L., and Conti, C. J., Induction of cyclin D1 overexpression by activated ras, Oncogene, 9, 3627-3633, 1994.
171. Liu, J. J., Chao, J. R., Jiang, M. C., Ng, S. Y., Yen, J. J., Yang-Yen, H. F., Ras transformation results in an elevated level of cyclin D1 and acceleration of G1 progression in NIH 3T3 cells, Mol. Cell. Biol., 15, 3654-3663, 1995.
172. Arber, N., Sutter, T., Miyake, M., Kahn, S. M., Venkatraj, V. S., Sobrino, A., Warburton, D., Holt, P. R., and Weinstein, I. B., Increased expression of cyclin D1 and the Rb tumor suppressor gene in c-K-ras transformed rat enterocytes, Oncogene, 1996; 12, 1903-1908, 1996.
173. Winston, J. T., Coats, S. R., Wang, Y. Z., and Pledger, W. J., Regulation of the cell cycle machinery by oncogenic ras, Oncogene, 12, 127-134, 1996.
174. Lavoie, J. N., L'Allemain, G., Brunet, A., Muller, R., and Pouyssegur, J., Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway, J. Biol. Chem., 271, 20608-20616, 1996.
175. Taylor, S. J. and Shalloway, D., Cell cycle-dependent activation of Ras, Curr. Biol., 6, 1621-1627, 1996.
176. Mittnacht, S., Paterson, H., Olson, M. F., and Marshall, C. J., Ras signaling is required for inactivation of the tumour suppressor pRb cell-cycle control protein, Curr. Biol., 7, 219-221, 1997.
177. Peeper, D. S., Upton, T. M., Ladha, M. H., Neuman, E., Zalvide, J., Bernards, R., DeCaprio, J. A., and Ewen, M. E., Ras signaling linked to the cell-cycle machinery by the retinoblastoma protein, Nature, 386, 177-181, 1997.
178. Aktas, H., Cai, H., and Cooper, G. M., Ras links growth factor signaling to the cell cycle machinery via regulation of cyclin D1 and the Cdk inhibitor p27KIP1, Mol. Cell. Biol., 17, 3850-3857, 1997.
179. Leone, G., DeGregori, J., Sears, R., Jakoi, L., and Nevins, J. R., Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F, Nature, 387, 422-426, 1997.
180. Galaktionov, K., Chen, X., and Beach, D., Cdc25 cell-cycle phosphatase as a target of c-myc, Nature, 382, 511-517, 1996.
181. Lloyd, A. C., Obermuller, F., Staddon, S., Barth, C. F., McMahon, M., and Land, H., Cooperating oncogenes converge to regulate cyclin/cdk complexes, Genes Dev., 11, 663-677, 1997.
182. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., and Lowe, S. W., Oncogenic ras provokes prema ture cell senescence associated with accumulation of p53 and p16INK4a, Cell, 88, 593-602, 1997.
183. Lin, H. J., Eviner, V., Prendergast, G. C., and White, E., Activated H-ras rescues E1A-induced apoptosis and cooperates with E1A to overcome p53-dependent growth arrest, Mol. Cell. Biol., 15, 4536-4544, 1995.
184. Nooter, K., Boersma, A. W., Oostrum, R. G., Burger, H., Jochemsen, A. G., and Stoter, G., Constitutive expression of the c-H-ras oncogene inhibits doxorubicin-induced apoptosis and promotes cell survival in a rhabdomyosarcoma cell line, Br. J. Cancer, 71, 556-561, 1995.
185. Gardner, A. M. and Johnson, G. L., Fibroblast growth factor-2 suppression of tumor necrosis factor alpha-mediated apoptosis requires Ras and the activation of mitogen-activated protein kinase, J. Biol. Chem., 271, 14560-14566, 1996.
186. McKenna, W. G., Bernhard, E. J., Markiewicz, D. A., Rudoltz, M. S., Maity, A., and Muschel, R. J., Regulation of radiation-induced apoptosis in oncogene- transfected fibroblasts: influence of H-ras on the G2 delay, Oncogene, 12, 237-245, 1996.
187. Fernandez, R. S., McGowan, A. J., and Cotter, T. G., Mutant H-ras overexpression inhibits drug and U.V.-induced apoptosis, Anticancer Res., 16, 1691-1705, 1996.
188. Kauffmann-Zeh, A., Rodriguez-Viciana, P., Ulrich, E., Gilbert, C., Coffer, P., Downward, J., and Evan, G., Suppression of c-Myc-induced apoptosis by Ras signaling through PI(3)K and PKB9 Nature, 385, 544-548, 1997.
189. Kinoshita, T., Yokota, T., Arai, K., and Miyajima, A., Suppression of apoptotic death in hematopoietic cells by signaling through the IL-3/GM-CSF receptors, EMBO J., 14, 266-275, 1995b.
190. Billadeau, D., Jelinek, D. F., Shah, N., LeBien, T. W., and Van, N. B., Introduction of an activated N-ras oncogene alters the growth characteristics of the interleukin 6-dependent myeloma cell line ANBL6, Cancer Res., 55, 3640-3646, 1995.
191. Gómez, J., Martínez-A, C., and Rebollo, A., Ras-mediated cell proliferation and cell death: some clues from the interleukin-2 receptor system, Apoptosis, 1, 175-182, 1996.
192. Gómez, J., Martínez-A, C., Fernandez, B., Garcia, A., and Rebollo, A., Critical role of Ras in the proliferation and prevention of apoptosis mediated by IL-2, J. Immunol., 157, 2272-2281, 1996.
193. Ferrari, G. and Greene, L. A., Proliferative inhibition by dominant-negative Ras rescues naive and neuronally differentiated PC12 cells from apoptotic death, EMBO J., 13, 5922-5928, 1994.
194. Gulbins, E., Bissonnette, R., Mahboubi, A., Martin, S., Nishioka, W., Brunner, T., Baier, G., Baier-Bitterlich, G., Byrd, C., Lang, F. et al., FAS-induced apoptosis is mediated via a ceramide-initiated RAS signaling pathway, Immunity, 2, 341-351, 1995.
195. Trent, J. C., 2nd, McConkey, D. J., Loughlin, S. M., Harbison, M. T., Fernández, A., and Ananthaswamy, H. N., Ras signaling in tumor necrosis factor-induced apoptosis, EMBO J., 143, 245-249, 1996.
196. di-Jeso, B., Ulianich, L., Racioppi, L., D'Armiento, F., Feliciello, A., Pacifico, F., Consiglio, E., and Formisano, S., Serum withdrawal induces apoptotic cell death in Ki ras transformed but not in normal differentiated thyroid cells, Biochem. Biophys. Res. Commun., 214, 819-824, 1995.
197. Wang, H. G., Millan, J. A., Cox, A. D., Der, C. J., Rapp, U. R., Beck, T., Zha, H., and Reed, J. C., R-Ras promotes apoptosis caused by growth factor deprivation via a Bcl-2 suppressible mechanism, J. Cell. Biol., 129, 1103-1114, 1995.
198. Gómez, J., Martínez, C., Fernández, B., García, A., and Rebollo, A., Ras activation leads to cell proliferation or apoptotic cell death on interleukin-2 stimulation or lymphokine deprivation, respectively, Eur. J. Immunol., 27, 1610-1618, 1997b.
199. Henkemeyer, M., Rossi, D. J., Puri, M. C., Mbamalu, G., Harpal, K., Shih, T. S., Jacks, T., and Pawson, T., Vascular system defects and neuronal apoptosis in mice lacking ras GTPase-activating protein, Nature, 377, 695-701, 1995.
200. Chen, C. Y. and Faller, D. V., Direction of p21ras-generated signals towards cell growth or apoptosis is determined by protein kinase C and Bcl-2, Oncogene, 11, 1487-1498, 1995.
201. Chen, C. Y. and Faller, D. V., Phosphorylation of Bcl-2 protein and association with p21Ras in Ras-induced apoptosis, J. Biol. Chem., 271, 2376-2379, 1996.
202. Gulbins, E., Coggeshall, K. M., Brenner, B., Schlottmann, K., Linderkamp, O., and Lang, F., Fas-induced apoptosis is mediated by activation of a Ras and Rac protein-regulated signaling pathway, J. Biol. Chem., 271, 26389-26394, 1996.
203. Gulbins, E., Brenner, B., Schlottmann, K., Welsch, J., Heinle, H., Koppenhoefer, U., Linderkamp, O., Coggeshall, K. M., and Lang, F., Fas-induced programmed cell death is mediated by a Ras-regulated O2-synthesis, Immunology, 89, 205-212, 1996.
204. Troppmair, J. and Rapp, U. R., Apoptosis regulation by Raf, Bcl-2, and R-Ras, Recent Results Cancer Res., 143, 245-249, 1997.
205. Spaargaren, M., Martin, G. A., McCormick, F., Fernández-Sarabia, M. J., and Bischoff, J. R., The Ras-related protein R-ras interacts directly with Raf-1 in a GTP-dependent manner, Biochem. J., 300, 303-307, 1994.
206. Evan, G. I., Brown, L., Whyte, M., and Harrington, E., Apoptosis and the cell cycle, Curr. Opin. Cell. Biol., 7, 825-834, 1995.
207. Nishizuka, Y., Protein kinase C and lipid signalling for sustained cellular responses, FASEB J., 9, 484-496, 1995.
208. Newton, A. C., Regulation of protein kinase C, Curr. Opin. Cell Biol., 9, 161-167, 1997.
209. Newton, A. C., Protein kinase C: structure, function and regulation, J. Biol. Chem., 5, 396-402, 1995.
210. Dekker, L. V., Palmer, R. H., and Parker, P. J., The protein kinase C and protein kinase C related gene families, Curr. Opin. Struct. Biol., 5, 396-402, 1995.
211. Zhang, G., Kazanietz, M. G., Blumberg, P. M., and Hurley, J. H., Crystal structure of the Cys2 activator-binding domain of protein kinase C δ in complex with phorbol ester, Cell, 81, 917-924, 1995.
212. Hanks, S. K. and Hunter, T., The eukaryotic protein kinase superfamily: kinase (catalitic) domain structure and classification, FASEB J., 9, 576-596, 1995.
213. Tsutakawa, S. E., Medzihradszky, K. F., Flint, A. J., Burlingame, A. L., and Koshland, D. E., Jr., Determination of in vivo phosphorylation sites in protein kinase C, J. Biol. Chem., 270, 26807-26812, 1995.
214. Keranen, L. M., Dutil, E. M., and Newton, A. C., Protein kinase C is regulated in vivo by three functionally distinct phosphorylations, Curr. Biol., 5, 1394-1403, 1995.
215. Clark, R. B., Love, J. T., Sgroi, D., Lingenheld, E. G., and Shaafi, R. I., The protein kinase C inhibitor H-7 inhibits antigen and IL-2-induced proliferation of murine T cell lines, Biochem. Biophys. Res. Commun., 145, 666-672, 1987.
216. Farrar, W. L. and Anderson, W. B., Interleukin-2 stimulates association of proteinkinase C with plasma membrane, Nature, 315, 233-235, 1985.
217. Gómez, J., de la Hera, A., Pitton, C., García, A., Silva, A., and Rebollo, A., Implication of protein kinase C in IL-2-mediated proliferation and apoptosis in a murine T cell clone, Exp. Cell. Res., 213, 178-182, 1994.
218. Gómez, J., Pitton, C., García, A., Martínez-A, C., Silva, A., and Rebollo, A., The zeta isoform of protein kinase C controls interleukin-2-mediated proliferation in a murine T cell line: evidence for an additional role of protein kinase C epsilon and beta, Exp. Cell. Res., 218, 105-113, 1995.
219. Mills, G., Girard, P., Grinstein, S., and Gelford, E. W., Interleukin-2 induces proliferation of T lymphocyte mutants lacking protein kinase C, Cell, 55, 92-100, 1988.
220. Redondo, J. M., López-Rives, A., Vila, V., Cragoe, E. J., and Fresno, M., The role of protein kinase C in lymphocyte proliferation. Existence of protein kinase C-dependent and -independent pathways, J. Biol. Chem., 163, 17467-17470, 1988.
221. Valge, V. E., Wong, J. G. P., Datlof, B. M., Sinskey, A. J., and Rao, A., Protein kinase C is required for responses to T cell receptor ligands but not to interleukin-2 in T cells, Cell, 55, 101-112, 1988.
222. James, G. and Olson, E., Deletion of the regulatory domain of protein kinase C alpha regions in the hinge and catalytic domain that mediate nuclear targeting, J. Cell. Biol., 116, 863-674, 1992.
223. Boyle, W. J., Smeal, T., Defice, L. H. K., Angel, P., Woodgett, J. R., Karin, M., and Hunter, T., Activation of protein kinase C decreases phosphorylation of c-jun at sites that negatively regulate its DNA-binding activity, Cell, 64, 573-584, 1991.
224. Baier-Bitterlich, G., Uberall, F., Bauer, B., Fresser, F., Wachter, H., Grunicke, H., Utermann, G., Altman, A., and Baier, G., Protein kinase C-theta isoenzyme selective stimulation of the transcription factor complex AP-1 in T lymphocytes, Mol. Cell. Biol., 16, 1842-1850, 1996.
225. Schamalz, D., Kalkbrenner, F., Hucho F., and Bruchner, K., Transport of protein kinase C alpha into the nucleus requires intact cytosqueleton while the transport of a protein containing a canonical nuclear localization signal does not, J. Cell. Sci., 109, 2401-2406, 1996.
226. Jaken, S., Protein kinase C isozymes and substrates, Curr. Opin. Cell. Biol., 8, 168-173, 1996.
227. Newton, A. C., Protein kinase C: ports of anchor in the cell, Curr. Biol., 6, 806-809, 1996.
228. Mochly-Rosen, D., Localization of protein kinases by anchoring proteins: a theme in signal transduction, Science, 268, 247-251, 1995.
229. Klauck, T. M., Faux, M. C., Labudda, K., Langeberg, L. K., Jaken, S., and Scott, J. D., Coordination of three signaling enzymes by AKAP 79, a mammalian scaffold protein, Science, 271, 1589-1592, 1996.
230. Acs, P., Szallasi, Z., Kazanietz, M. G., and Blumberg, P. M., Differential activation of PKC isozymes by 14-3-3 ζ protein, Biochem. Biophys. Res. Commun., 216, 103-109, 1995.
231. Prekeris, R., Mayhew, M. W., Cooper, J. B., and Terrian D. M., Identification and localization of an actin-binding motif that is unique to the epsilon isoform of protein kinase C and participates in the regulation of synaptic function, J. Cell. Biol., 132, 77-90, 1996.
232. Blobe, G. C., Stribling, D. S., Fabbro, D., Stabel, S., Hannun, Y. A., Protein kinase C β II specifically binds to and is activated by F-actin, J. Biol. Chem., 271, 15823-15830, 1996.
233. Gómez, J., Martínez-A, C., García, A., and Rebollo, A., Association of phosphatidylinositol 3 kinase to protein kinase C ζ during interleukin-2 stimulation, Eur. J. Immunol., 26, 1781-1787, 1996b.
234. Lehrich, R. W. and Forrest, J. N., Protein kinase C zeta is associated with the mitotic apparatus in primary cell cultures of the shark rectal gland, J. Biol. Chem., 269, 32446-32450, 1994.
235. Konishi, H., Kuroda, S., and Kikkawa, U., The pleckstrin homology domain of RAC protein kinase associates with the regulatory domain of protein kinase C zeta, Biochem. Biophys. Res. Commun., 205, 1770-1775, 1994.
236. Cai, H., Smola, U., Wixler, V., Eissenmann-Tappe, I., Diaz-Meco, M. T., Moscat, J., Rapp, U., and Cooper, G. M., Role of dyacilglycerol-regulated protein kinase C isotypes in growth factor activation of the Raf-1 protein kinase, Mol. Cell. Biol., 17, 732-741, 1997.
237. Derman, M. P., Toker, A., Hartwig, J. H., Spokes, K., Falck, J. R., Chen, C.-S., Cantley, L.C., and Cantley, Ll.G., The lipids products of phosphoinositide 3-kinase increase cell motility through protein kinase C, J. Biol. Chem., 272, 6465-6470, 1997.
238. kip1 and hypophosphorilation of the retinoblastoma protein in intestinal epithelial cells, J. Biol. Chem., 272, 9424-9435, 1997.
239. 2+ entry in jurkat T cells, J. Biol. Chem., 272, 15426-15433, 1997.
240. Ridley, A. J., Rho-related proteins: actin cytoskeleton and cell cycle, Curr. Opin. Genet. Dev., 5, 24-30, 1995.
241. Narumiya, S., The small GTPase Rho: cellular functions and signal transduction, J. Biochem., 120, 215-228, 1996.
242. Burbelo, P. D., Miyamoto, A., Utani, S., Brill, K. M., Yamada, A., Hall, A., and Yamada, Y., p190-B, a new member of the Rho-GAP family, and Rho are induced, to cluster after integrin cross-linking, J. Biol. Chem., 170, 30919-30926, 1995.
243. Tribioli, C., Droetto, S., Bione, S., Cesareni, G., Torrisi, M. R., Lotti, L. V., Laufrancone, L., Toniolo, D., and Pelicci, P., An X chromosome linked gene encoding a protein with characteristics of a Rho-GAP predominantly expressed in hematopoietic cells, Proc. Natl. Acad. Sci. U.S.A., 93, 659-699, 1996.
244. Hart, M. J., Sharma, S., Masry, N., Qiu, R. G., McCabe, P., Polakis, P., and Bollag, G., Identification of a novel guanine nucleotide exchange factor for the Rho GTPase, J. Biol. Chem., 271, 25452-25458, 1996.
245. Chuang, T. H., Xu, X., Kaartinen, V., Heisterkamp, N., Groffen, J., and Bockoch, G. M., Abr and Bcr are multifunctional regulators of the Rho-GTP binding protein family, Proc. Natl. Acad. Sci. U.S.A., 92, 10282-10286, 1995.
246. Han, J., Das, B., Wei, W., Van-Aelst, L., Mosteller, R. D., Khosravi, R., Westwck, J. K., Der, C. J., and Broek, D., Lck regulates Vav activation of members of the Rho family GTPases, Mol. Cell. Biol., 17, 1346-1353, 1997.
247. Ridley, A. J. and Hall, A., Signal transduction pathways regulating Rho-mediated stress fiber formation. Requirement for a tyrosine kinase, EMBO J., 13, 2600-2610, 1994.
248. Zhang, J., King, W. G., Dillon, S., Hall, A., Feig, L., and Rittenhouse, S. E., Activation of platelet phosphatidylinositide 3-kinase requires the small GTP-binding protein Rho, J. Biol. Chem., 268, 22251-22254, 1993.
249. Reif, K., Nobes, C. D., Thomas, G., Hall, A., and Cantrell, D. A., PI3 kinase signals activate a selective subset of Rac/Rho-dependent effectors pathways, Curr. Biol., 6, 1445-1455, 1996.
250. Schmidt, M., Rumenapp, U., Bienek, C., Keller, J., Eichel-Streiber, C., and Jakobs, K. H., Inhibition of receptor signaling to PLD by C. difficile toxin B. Role of Rho proteins, J. Biol. Chem., 271, 2422-2426, 1996.
251. Hess, J. A., Ross, A. H., Qin, R. G., Symons, M., and Exton, J. H., Role of Rho family proteins in PLD activation by growth factors, J. Biol. Chem., 272, 1615-1620, 1997.
252. Vincent, S. and Settleman, J., The PRK2 kinase is a potential effector target of both Rho and Rac GTPases and regulates actin cytoskeletal organization, Mol. Cell. Biol., 17, 2247-2256, 1997.
253. Amano, M., Mukai, H., Ono, Y., Chihara, K., Matsui, T., Hamajima, Y., Okawa, K., Iwamatsu, A., and Kaibuchi, K., Identification of a putative target for Rho as the reine-threonine kinase protein kinase N, Science, 271, 648-650, 1996.
254. Watanabe, G., Saite, Y., Madaule, P., Ishizaki, T., Fujisawa, K., Morii, N., Mukai, H., Ono, Y., Kakizuka, A., and Narumiya, S., Protein kinase N (PKN) and PKN-related protein rhophilinas targets of small GTPase Rho, Science, 271, 645-647, 1996.
255. Reid, T., Furuyashiki, T., Ishizaki, T., Watanabe, G., Watanabe, N., Fujisawa, K., Morii, N., Madaule, P., and Narumiya, S., Rhotekin, a new putative target for Rho bearing homology to a serine/threonine kinase PKN, and rhophilin in the Rho-binding domain, J. Biol. Chem., 271, 13556-13560, 1996.
256. Leung, T., Mauser, Z., Tau, L., and Lin, L., A novel serine/threonine kinase binding the Ras-related RhoA GTPase which translocates the kinase to peripheral membrane, J. Biol. Chem., 270, 29051-29054, 1995.
257. Amano, M., Chichara, K., Kimura, K., Fukata, Y., Nakamura, M., Matsuura, Y., and Kaibuchi, K., Identification of a putative target for Rho as the serine/threonine kinase protein kinase N, Science, 275, 1308-1313, 1997.
258. Gómez, J., García, A., R.-Borlado, L., Bonay, P., Martinez-A, C., Silva, A., Fresno, M., Carrera, A. C., Eicher-Streiber, C., and Rebollo, A., IL-2 signaling controls actin organization through Rho-like protein family, phosphatidylinositol 3-kinase, and protein kinase C-ζ, J. Immunol., 158, 1516-1522, 1997.
259. Teramoto, H., Crespo, P., Coso, O. A., Igishi, T., Xu, N., and Gutkind, J. S., The small GTP-binding protein Rho activates c-jun N-terminal kinases/stress-activated protein kinases in human kidney 29 3T cells. Evidence for a Pak independent pathway, J. Biol. Chem., 271, 25731-25734, 1996.
260. Frost, J. A., Xu, S., Hutchison, M. R., Marcus, S., and Cobb, M. H., Actions of Rho family small G proteins and p21-activated protein kinases an mitogen-activated protein kinase family members, Mol. Cell. Biol., 16, 3707-3713, 1996.
261. Perona, R., Moutauer, S., Saniger, L., Sanchez-Pérez, I., Bravo, R., and Lacal, J. C., Activation of NF-κB by Rho, Cdc42 and Rac-1 proteins, Genes Dev., 11, 463-475, 1997.
262. Moorman, J. P., Bobak, D. A., and Hahn, C. S., Inactivation of the small GTP binding prtein Rho induces multinucleate cell formation and apoptosis in murine T lymphoma EL4, J. Immunol., 156, 4146-4153, 1996.
263. Hirai, A., Nakamura, S., Naguchi, Y., Yasuda, T., Kitagawa, M., Tatsuno, I., Oeda, E., Tahara, K., Trano, T., Narumiya, S., Kohan, L. D., and Saito, T., Geranylgeranylated Rho GTPases are essential for the degradation of p27 kip1 and facilitate the progression from G1 to S phase in growth-stimulated rat FRTL-5 cells, J. Biol. Chem., 272, 13-16, 1997.
264. Henning, S. W., Golandrini, R., Hall, A., and Cantrell, D. A., The GTPase Rho has a critical regulatory role in thymus development, EMBO J., 16, 2397-2407, 1997.
265. Lebowitz, P, F., Du Wei, and Prendergast, G. C., Prenylation of Rho B is required for its cell transformation function but not its ability to activate serum response element-dependent transcription, J. Biol. Chem., 272, 16093-16095, 1997.
266. Qiu, R. G., Chen, J., Kirn, D., McCormick, F., and Symons, M., An essential role for Rac in Ras transformation, Nature, 374, 457-459, 1995.
267. Qiu, R. G., Chen, J., McCormick, F., and Symons, M., A role for Rho in Ras transformation, Proc. Natl. Acad. Sci. U.S.A., 92, 11781-11785, 1995.
268. Esteve, P., Peso, L., and Lacal, J. C., Induction of apoptosis by Rho in NIH3T3 cells requires two complementary signals, Oncogene, 11, 2657-2665, 1995.
269. Jimenez, B., Arend, M., Esteve, P., Perona, R., Sanchez, R., Ramon y Cajal, S., Wyllie, A., and Lacal, J. C., Induction of apoptosis in NIH3T3 cells after serum deprivation by overexpression of Rho-p21, a GTPase protein of the Ras superfamily, Oncogene, 10, 811-816, 1995.
270. Henning, S. W., Galandrini, R., Hall, A., and Cantrell, D. A., The GTPase Rho has a critical regulatory role in thymus development, EMBO J., 16, 2397-2407, 1977.
271. Fry, M. J., Panayotou, G., Dhand, R., Ruiz-Larrea, F., Gout, I., Nguyen, O., Courtheidge, G., and Waterfield, M. D., Purification and characterization of a phosphatidylinositol 3-kinase complex from bovine brain by using phosphopeptide affinity colums, Biochem. J., 288, 383-393, 1993.
272. Hiles, I. D., Otsu, M., Volinai, S., Fry, M. J., Gout, I., Dhand, R., Panayotou, G., Ruiz-Larrea, F., Thompson, A., Torry, N. F., Hsuan, J. J., Courtneidge, S. A., Parker, P. J., and Waterfield, M. D., Phosphatidylinositol 3-kinase: structure and expression of the 110 kd catalytic subunit, Cell, 70, 419-429, 1992.
273. Hunter, T., When is a lipid kinase not a lipid kinase? when it is a protein kinase, Cell, 83, 1-4, 1995.
274. Pawson, T. and Gish, G. D., SH2 and SH3 domains: from structure to function, Cell, 71, 359-362, 1992.
275. Klipper, A., Escobedo, J. A., Fantl, W. J., and Willimas, L. T., The C-terminal SH2 domain of p85 accounts for the high affinity and specificity of the binding of phosphatidylinositol 3-kinase to phosphorylated platelet-derived growth factor beta receptor, Mol. Cell. Biol., 12, 1451-1459, 1992.
276. McGlade, C. J., Ellis, C., Reedijk, M., Anderson, D., Mbamulu, G., Reith, A., Panayotou, G., End P., Bertein, A., Kazlauskas, A., Waterfield, M., and Pawson, T., SH2 domains of the p85 alpha subunit of phosphatidylinositol 3-kinase regulate binding to growth factor receptors, Mol. Cell. Biol., 12, 991-997, 1992.
277. Inukai, K., Funaki, M., Ogihara, T., Katagiri, H., Kanda, A., Anai, M., Fukushima, Y., Hosaka, T., Suzuki, M., Shin, B-C., Takata, K., Yazaki, Y., Kikuchi, M., Oka, Y., and Asano, T., p85α gene generates three isoforms of regulatory subunit for phosphatidylinositol 3-kinase (PI 3-kinase), p50α, p55α, and p85α, with different PI 3-kinase activity elevating responses to insulin, J. Biol. Chem., 272, 7873-7882, 1997.
278. Antonetti, D., Algenstaedt, P., and Khan, C. R., Insulin receptor substrate 1 binds two novel splice variants of the regulatory subunit of phosphatidylinositol 3-kinase in muscle and brain, Mol. Cell. Biol., 16, 2195-2103, 1996.
279. Pons, S., Asano, T., Glasheen, E., Miralpeix, M., Zhang, Y., Fisher, T. L., Myers, M. G., Sun, X. J., and White, M. F., The structure and function of p55PIK reveal a new regulatory subunit for phosphatidylinositol 3-kinase, Mol. Cell. Biol., 15, 4453-4465, 1995.
280. Franke, T. F., Yang, S. I., Chan, T. O., Datta, K., Kazlauskas, A., Morrison, D. K., Kaplan, D. R., and Tsichlis, P. N., The protein kinase encoded by Akt protooncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase, Cell, 81, 723-736, 1995.
281. Hawkins, P. T., Eguinoa, A., Qui, R. G., Stokoe, D., Cooke, F. T., Walters, R., Wennstrom, S., Claesson, W. L., Evans, T., and Symons, M., PDGF stimulates an increase in GTP-Rac via activation of phosphoinositide 3-kinase, Curr. Biol., 5, 393-403, 1995.
282. Dahl, J., Freund, R., Blenis, J., and Benjamin, T. L., Studies of partially transforming polyomavirus mutants establish a role for phosphatidylinositol 3-kinase in activation of pp70 S6 kinase, Mol. Cell. Biol., 16, 2728-2735, 1996.
283. Cheatham, B., Vlahos, C. J., Cheatham, L., Wang, L., Blenis, J., and Kahan, C., Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation, Mol. Cell. Biol., 14, 4902-4911, 1994.
284. Gold, M. R., Duronio, V., Saxena, S. P., Schrader, J. W., and Aebersold, R., Multiple cytokines activate phosphatidylinositol 3-kinase in hematopoietic cells. Association of the enzyme with various tyrosine-phosphorylated proteins, J. Biol. Chem., 269, 5403-5412, 1994.
285. Kimura, K., Hattori, S., Kabuyama, Y., Shizawa, Y., Takayanagi, J., Nakamura, S., Toki, S., Matsuda, Y., Onodera, K., and Fukui, Y., Neurite outgrowth of P12 cells is suppressed by wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase, J. Biol. Chem., 269, 18961-18967, 1994.
286. Wennstrom, S., Hawkins, P., Cooke, F., Hara, K., Yonezawa, K., Kasuga, M., Jackson, T., Claesson-Welsh, L., and Stephens, L., Activation of the phosphoinositide 3-kinase is required for PDGF-stimulated membrane ruffling, Curr. Biol., 4, 385-393, 1994.
287. Yao, R. and Cooper, G. M., Requirement for phosphatidylinositol 3-kinase in the prevention of apoptosis by nerve growth factor, Science, 267, 2003-2006, 1995.
288. Kanai, F., Ito, K., Todaka, M., Hayashi, H., Kamohara, S., Ishii, K., Okada, T., Hazeki, O., Ui, M., and Ebina, E., Insulin-stimulated GLUT4 translocation is relevant to the phosphorylation of IRS-1 and the activity of PI3-kinase, Biochem. Biophys. Res. Commun., 195, 762-768, 1993.
289. Rodriguez-Viciana, P., Warne, P. H., Khawaja, A., Marte, B. M., Pappin, D., Das, P., Waterfield, M. D., Ridley, A., and Downward, J., Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras, Cell, 89, 457-467, 1997.
290. Fukui, Y. and Hanafusa, H., Phosphatidylinositol kinase activity associates with viral p60 src protein, Mol. Cell. Biol., 9, 1651-1658, 1989.
291. Williams, L. T., Signal transduction by the platelet-derived growth factor receptor, Science, 243, 1564-1570, 1989.
292. Varticovski, L., Druker, B., Morrison, D., Cantley, L., and Roberts, T., The colony stimulation factor-1 receptor associates with and activates phosphatidylinositol-3 kinase, Nature, 342, 699-702, 1989.
293. Bjorge, J. E., Chan, T. O., Antczak, M., Kung, H. T., and Fujita, D. J., Activated type 1 phosphatidylinositol kinase is associated with the epidermal growth factor (EGF) receptor following EGF stimulation, Proc. Natl. Acad. Sci. U.S.A., 87, 3816-3820, 1990.
294. Lev, S., Givol, M. D., and Yarden, Y., A specific combination of substrates is involved in signal transduction by the kit-encoded receptor, EMBO J., 10, 647-654, 1991.
295. Karnitz, L. M., Sutor, S. L., and Abraham, R. T., The Src-family kinase, Fyn, regulates activation of phosphatidylinositol 3-kinase in an interleukin 2-responsive T cell line, J. Exp. Med., 179, 1799-1804, 1994.
296. Reif, K., Burgering, B. M. T., and Cantrell, D. A., Phosphatidylinositol 3-kinase links the interleukin-2 receptor to protein kinase B and p70 S6 kinase, J. Biol. Chem., 272, 14426-14433, 1997.
297. Scheid, M. P. and Duronio, V., Phosphatidylinositol 3-OH kinase activity is not required for activation of mitogen-activated protein kinase by cytokines, J. Biol. Chem., 271, 18134-18139, 1996.
298. Truitt, K. E., Mills, G. B., Turck, C. W., and Imboden, J. B., SH2-dependent association of phosphatidylinositol 3′-kinase 85-kDa regulatory sub- unit with the interleukin-2 receptor β chain, J. Biol. Chem., 269, 5937-5943, 1994.
299. González-García, A., Mérida, I., Martinez-A, C., and Carrera, A. C., Intermediate affinity interleukin- 2 receptor mediates survival via a phosphatidylinositol 3-kinase-dependent pathway, J. Biol. Chem., 272, 10220-10226, 1997.
300. López-Ilasaca, M., Li, W., Uren, A., Yu, J. C., Kazlauskas, A., Gutkind, J. S., and Heidaran, M. A., Requirement of phosphatidylinositol-3 kinase for activation of JNK/SAPKs by PDGF, Biochem. Biophys. Res. Commun., 232, 273-277, 1997.
301. Zhang, Q. X., Davis, I. D., and Baldwin, G. S., Controlled overexpression of selected domains of the p85 subunit of phosphatidylinositol 3-kinase reverts v-Ha-Ras transformation, Biochem. Biophys. Acta, 1312, 207-214, 1996.
302. Jascur, T., Gilman, J., and Mustelin, T., Involvement of phosphatidylinositol 3-kinase in NFAT activation in T cells, J. Biol. Chem., 272, 14483-14488, 1997.
303. McIlroy, J., Chen, D., Wjasow, C., Michaeli, T., and Backer, J. M., Specific activation of p85-p110 phosphatidylinositol 3′-kinase stimulates DNA synthesis by ras- and p70 S6 kinase-dependent pathways, Mol. Cell. Biol., 17, 248-255, 1997.
304. Sabatini, D. M., Pierchala, B. A., Barrow, R. K., Schell, M. J., and Snyder, S. M., The rapamycin and FKBP 12 target (RAFT) displays phosphatidylinositol 4-kinase activity, J. Biol. Chem., 270, 20875-20878, 1995.
305. Abraham, R.T., Phosphatidylinositol 3-kinase related kinases, Curr. Opin. Immunol., 8, 412-418, 1996.
306. Weinert, T. A., Kiser, G. L., and Hartwell, L. H., Mitotic checkpoints genes in budding yeast and the dependence of mitosis on DNA replication and repair, Genes Dev., 8, 652-665, 1994.
307. Paulovich, A. G. and Hartwell, L. H., A checkpoint regulates the rate of progression through S phase in S. cerevisiae in response to DNA damage, Cell, 82, 841-847, 1995.
308. Greenwell, P. W., Kronmal, S. L., Porter, S. E., Gassenhuber, J., Obermaier, B., and Petes, T. D., TEL1, a gene involved in controlling telomere length in S, cerevisiae, is homologous to the human ataxia telangiectasia gene, Cell, 82, 823-829, 1995.
309. Sanchez, Y., Desany, B. A., Jones, W. J., Liu, Q., Wang, B., and Elledge, S. J., Regulation of RAD53 by the ATM-like kinases MEC1 and TEL 1 in yeast cell cycle checkpoint pathways. Science, 271, 357-360, 1996.
310. Finnie, N. J., Gottlieb, T. M., Blunt, T., Jeggo, P., and Jackson, S. P., DNA-PK activity is absent in xrs-6 cells: implications for site-specific recombination and DNA double-strand break repair, Proc. Natl. Acad. Sci. U.SA. 92, 320-324, 1995.
311. Jeggo, P. A., Taccioli, G. E., and Jackson, S. P., Menage à trois - double strand break repair, V(D)J recombination and DNA-PK, Bioessays, 17, 49-957, 1995.
312. Swift, M., Chase, C. L., and Morrell, D., Cancer predisposition of ataxia-telangiectasia heterozygotes, Cancer Genet. Cytogenet., 46, 21-27, 1990.
313. Swift, M., Morrell, D., Massey, R. B., and Chase, C. L., Incidence of cancer in 161 families affected by ataxia-telangiectasia, N. Engl. J. Med. 325, 1831-1836, 1991.
314. Schmidt, A., Bickle, M., Beck, T., and Hall, M. N., The yeast phosphatidylinositol kinase homolog TOR2 activates RHO1 and RHO2 via the exchange factor ROM2, Cell, 88, 531-542, 1997.
315. Burgering, B. M. T. and Coffer, P. J., Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction, Nature, 376, 599-602, 1995.
316. Kohn, A. D., Kovacina, K. S., and Roth, R. A., Insulin stimulates the kinase activity opf RAC-PK, a pleckstrin homology domain containing ser/thr kinase, EMBO J., 14, 4288-4298, 1995.
317. Bos, J. L., A target for phosphoinositide 3-kinase: Akt/PKB, Trends Biochem. Sci., 20, 441-442, 1995.
318. Haslam, R. J., Koide, H. B., and Hemmings, B. A., Pleckstrin domain homology, Nature, 363, 309-310, 1993.
319. Bellacosa, A., Testa, J. R., Staal, S. P., and Tsichlis, P. N., A retroviral oncogene, Akt, encoding a serine threonine kinase containing an SH2-like region, Science, 254, 274-277, 1991.
320. Franke, T. F., Kaplan, D. R., Cantley, L. C., and Toker, A., Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate, Science, 275, 665-668, 1997b.
321. Klippel, A., Kavanaugh, W. M., Pot, D., and Williams, L. T., A specific product of phosphatidylinositol 3-kinase directly activates the protein kinase Akt through its pleckstrin homology domain, Mol. Cell. Biol., 17, 338-344, 1997.
322. Stokoe, D., Stephens, L. R., Copeland, T., Gaffney, P. R. J., Reese, C. B., Painter, G. F., Holmes, A. B., McCormick, F., and Hawkins, P. T., Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B, Science, 277, 567-570, 1997.
323. Kohn, A. D., Takeuchi, F., and Roth, R. A., Akt, a pleckstrin homology domain containing kinase, is activated primarily by phosphorylation, J. Biol. Chem., 271, 21920-21926, 1996.
324. Kohn, A. D., Summers, S. A., Birnbaum, M. J., and Roth, R. A., Expression of a constitutively active Akt ser/thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation, J. Biol. Chem., 271, 31372-31378, 1996.
325. Ahmed, N. N., Grimes, H. L., Bellacosa, A., Chan, T. A., and Tsichlis, P. N., Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase, Proc. Natl. Acad. Sci. U.S.A., 94, 3627-3632, 1997.
326. Franke, T. F., Kaplan, D. R., and Cantley, L. C., PI3K: downstream AKTion blocks apoptosis, Cell, 88, 435-437, 1997a.
327. Kulik, G., Klippel, A., and Weber, M. J., Antiapoptotic signalling by the insulin-like growth factor 1 receptor, phosphatidylinositol 3-kinase, and Akt, Mol. Cell. Biol., 17, 1595-1606, 1997.
328. Kauffmann-Zeh, A., Rodriguez-Viciana, P., Ulrich, E., Gilbert, E., Coffer, P., Downward, J., and Gerard, E., Suppression of c-Myc-induced apoptosis by Ras signaling through PI(3)K and PKB, Nature, 385, 544-548, 1997.
329. Hemmings, B. A., Akt signalling: linking membrane events to life and death decisions, Science, 275, 628-630, 1997.
330. Xia, Z., Dickens, M., Raingeaud, J., Davis, R. J., and Greenberg, M. E., Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis, Science, 270, 1326-1331, 1995.
331. Zanke, B. W., Boudreau, K., Rubie, E., Winnett, E., Tibbes, L. A., Zon, L., Kyriakis, J., Liu, F. F., and Woodgett, J. R., The stress-activated protein kinase pathway mediates cell death following injury induced by cis-platinum, UV irradiation or heat, Curr. Biol., 6, 606-613, 1996.
332. Englaro, W., Rezzonico, R., Durand-Clement, M., Lallemand, D., Ortonne, J. P., and Balloti, R., Mitogen-activated protein kinase pathway and AP-1 are activated during cAMP induced melanogenesis in B-16 melano cells, J. Biol. Chem., 270, 24315-24320, 1995.
333. Gille, H., Strahl, T., and Shaw, P. E., Activation of ternary complex factor Elk-1 by stress-activated protein kinases, Curr. Biol., 5, 1191-1200, 1995.
334. Zinck, R., Cahill, M. A., Kracht, M., Sachsenmaier, C., Hipskind, R. A., and Nordheim, A., Protein synthesis inhibitors reveal differential regulation of mitogen-activated protein kinase and stress-activated protein kinase pathways that converge on Elk-1, Mol. Cell. Biol., 15, 4930-4938, 1995.
335. Janknecht, R. and Hunter, T., Activation of the Sap-la transcription factor by the c-jun N-terminal kinase (JNK) mitogen-activated protein kinase, J. Biol. Chem., 272, 4219-4224, 1997.
336. Cavigelli, M., Dolfi, F., Claret, F-X., and Karin, M., Induction of c-fos expression through JNK-mediated TCF/Elk-1 phosphorylation, EMBO J., 14, 5957-5964, 1995.
337. Gupta, S., Barrett, T., Whitmarsh, A. J., Cavanagh, J., Sluss, K., Dérijard, B., and Davis, R. J., Selective interaction of INK protein kinase isoforms with transcription factors, EMBO J., 15, 2760-2770, 1996.
338. Bird, T. A., Kyriakis, J. M., Tyshler, L., Gayle, M., Milne, A., and Virca G, D., Interleukin-1 activates p54 mitogen-activated protein kinase by a pathway thst is independent of p21Ras, Raf-1, and MAP kinase kinase, J. Biol. Chem., 269, 31836-31844, 1994.
339. Kracht, M., Truong, O., Totty, N. F., Shiroo, M., and Saklatvala, J., Interleukin-1 alpha activates two forms of p54 alpha mitogen-activated protein kinase in rabbit liver, J. Exp. Med., 180, 2017-2025, 1994.
340. Matsuda, S., Kawasaki, H., Moriguchi, T., Gotoh, Y., and Nishida, E., Activation of protein kinase cascades by osmotic shock, J. Biol. Chem., 270, 12781-12786, 1995.
341. Adler, V., Schaffer, A., Kim, J., Dolan, L., and Ronai, Z., UV irradiation and heat shock mediate JNK activation via alternate pathways, J. Biol. Chem., 270, 26071-26077, 1995.
342. Atfi, A., Djelloul, S., Chastre, E., Davis, R., and Gespach, C., Evidence for a role of Rho-like GTPases and stress-activated protein kinase/c-jun N-terminal kinase (SAPK/JNK) in transforming growth factor beta-mediated signaling, J. Biol. Chem., 272, 1429-1432, 1997.
343. Dérijard, B., Raingeaud, J., Barrett, T., Wu, I. H., Han, J., Ulevich, R. J., and Davis, R. J., Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms, Science, 267, 682-685, 1995.
344. Olson, M. F., Ashworth, A., and Hall, A., An essential role for Rho, Rac, and Cdc42 GTPases in cell cycle progression through G1, Science, 269, 1270-1272, 1995.
345. Minden, A., Lin, A., Claret, F-X., Abo, A., and Karin, M., Selective activation of the JNK signaling cascade and c-jun transcriptional activity by the small GTPases Rac and Cdc42Hs, Cell, 81, 1447-1457, 1995.
346. Coso, O. A., Chiariello, M., Yu, J-C., Teramoto, H., Crespo, P., Xu, N., Miki, T., and Gutkind, J. S., The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway, Cell, 81, 1137-1146, 1995.
347. Dickens, M., Rogers, J. S., Cavanagh, J., Raitano, A., Xia, Z., Halpern, J. R., Greenberg, M. E., Sawyers, C. L., and Davis, R. J., A cytoplasmic inhibitor of the JNK signal transduction pathway, Science, 277, 693-696, 1997.
348. Ichijo, H., Nishida, E., Irie, K., Dijke, P., Saitoh, M., Moriguchi, T., Takagi, M., Matsumoto, K., Miyazono, K., and Gotoh, Y., Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways, Science, 275, 90-94, 1997.
349. Verheij, M., Bose, R., Lin, X. H., Yao, B., Jarvis, W. D., Grant, S., Birrer, M. J., Szabo, E., Zon, L. I., Kyriakis, J. M., Haimovitz-Friedman, A., Fuks, Z., and Kolesnick, R. N., Requirement for ceramide-initiated SAPK/JNK signaling in stress-induced apoptosis, Nature, 380, 75-79, 1996.
350. Su, B., Jacinto, E., Hibi, M., Kallunki, T., Karin, M., and Ben-Neriah, Y., JNK is involved in signal integration during costimulation of T lymphocytes, Cell, 77, 727-736, 1994.
351. Tibbles, L. A., Ing, Y. L., Kiefer, F., Chan, J., Iscove, N., Woodgett, J. R., and Lassam, N. J., MLK-3 activates the SAPK/JNK and p38/RK pathways via SEK1 and MKK3/6, EMBO J., 15, 7026-7035, 1996.
352. Hoey, T., Sun, Y. L., Williamson, K., ans Xu, X., Isolation of two new members of the NF-AT gene family and functional characterization of the NF-AT proteins, Immunity, 2, 461-472, 1995.
353. Masuda, E. S., Naito, Y., Tokimitsu, H., Campbell, D., Seito, F., Hannum, C., Arai, K., and Arai, N., NF-ATx, a novel member of the nuclear factor of activated T cells family that is expressed predominently in the thymus, Mol. Cell. Biol., 15, 2697-2706, 1995.
354. Northrop, J. P., Ho, S. N., Chen, L., Thomos, D. J., Timmerman, L. A., Nolan, G. P., Admon, A., and Crabtrere, G. R., NF-AT components define a family of transcription factors targeted in T-cell activation, Nature, 369, 497-502, 1994.
355. Rooney, J. W., Hoey, T., and Glincher, L. H., Coordinate and cooperative roles for NF-AT and AP-1 in the regulation of the murine IL-4 gene, Immunity, 2, 473-483, 1995.
356. Rao, A., NF-ATp: a transcription factor required for the coordinate induction of several cytokine genes, Immunol. Today, 15, 274-281, 1994.
357. + Th2 cells but not in Th1 cells, Mol. Cell. Biol., 17, 1522-1534, 1997.
358. Hodge, M. R., Rauger, A. M., de la Brousse, F. C., Hoery, T., Grusby, M. J., and Glimber, L. H., Hyperproliferation and dysregulation of IL-4 expression in NF-ATp-deficient mice, Immunity, 4, 397-405, 1996.
359. Park, J. H. and Levitt, L., Overexpression of mitogen-activated protein kinase (ERK1) enhances T-cell cytokine gene expression: role of AP1, NF-AT, and NF-κB, Blood, 82, 2470-2477, 1993.
360. Jain, J., McCaffrey, P. G., Miner, A., Kerppola, T. K., Lambert, J. N., Verdine, G. L., Curram, T., and Kao, A., The T cell transcription factor NF-ATp is a substrate for calcineurin and interacts with Fos and Jun, Nature, 365, 353-355, 1993.
361. Emmel, E. A., Verweij, C. L., Durand, D. B., Higgins, K. M., Lacy, E., and Crabtree, G. R., Cyclosporin A specifically inhibits function of nuclear proteins involved in T cell activation, Science, 1246, 1617-1620, 1989.
362. Flanagan, W. F., Corthesy, B., Bram, R. J., and Crabtree, G. R., Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A, Nature, 352, 803-807, 1991.
363. Muramatsu, T. and Kiucaid, R. L., Inhibition of NF-AT signal transduction events by a dominant-negative form of calcineurin, Biochem. Biophys. Res. Commun., 218, 466-472, 1996.
364. Shibasaki, F., Price, E. R., Milan, D., and McKeon, F., Role of kinases and the phosphatase calcineurin in the nuclear shuttling of transcription factor NF-AT4, Nature, 392, 370-373, 1996.
365. Gómez, J., Martínez-A, C., González, A., García, A., and Rebollo, A., The Bcl-2 gene is differentially regulated by IL-2 and IL-4 through the transcription factor NF-AT, submitted.
366. Sen, R. and Baltimore, p., Multiple nuclear factors Intact with the immunoglobulin enhancer sequences, Cell, 46, 705-716, 1986.
367. Baeuerle, P. A. and Henkel, T., Function and activation of NF-κB in the immune system, Annu. Rev. Immunol., 12, 141-179, 1994.
368. Israel, A., A role for phosphorylation and degradationin the control of NF-κB activity, Trends. Genet., 11, 203-205, 1995.
369. Beg, A. and Baldwin, A., The IκB proteins: multi-functional regulators of Rel/NF-κB transcription factors, Genes Dev., 7, 2064-2070, 1993.
370. Finco, T. and Baldwin, G., Regulation of NF-κB: the emerging roles of phosphorylation and proteolysis, Immunity, 3, 263-272, 1995.
371. Grant, A. J., Roessler, E., Ju, G., Tsudo, M., Sugamura, K., and Waldmann, T. A., The interleukin 2 receptor (IL-2R): the TL-2R alpha subunit afters the function of the IL-2R beta subunit to enhance IL-2 binding and signaling by mechanisms that do not require binding of IL-2 to IL-2R alpha subunit, Proc. Natl. Acad. Sci. U.S.A., 89, 2165-2169, 1992.
372. Sha, W. C., Liou, H. C., Tuomanen, E. I., and Baltimore, E., Targeted disruption of the p50 subunit of NF-κB leads to multifocal defects in immature responses, Cell, 80, 321-330, 1995.
373. Beg, A. A., Sha, W. C., Bronson, R. T., Ghosh, S., and Baltimore, D., Embryonic lethality and liver degeneration in mice lacking de Rel A component of NF-κB, Nature, 376, 167-170, 1995.
374. Weih, F., Carrasco, D., Durham, S. K., Batron, D. S., Rozzo, C. A., Ryseck, R. P., Lira, S. A., and Bravo, R., Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of Rel B, a member of the NF-κB/Rel family, Cell, 80, 331-340, 1995.
375. Burkly, L., Hession, C., Ogata, L., Reilly, C., Marconi, L. A., Olson, D., Tizard, R., Cate, R., and Lo, D., Expression of Rel B is required for the development of thymic medulla and dendritic cells, Nature, 373, 531-536, 1995.
376. Miyamoto, S., Chiao, P. J., and Verma, M., Enhanced IκBα degradation is responsible for constitutive NF-κB activity in mature murine B cell lines, Mol. Cell. Biol., 14, 3276-3282, 1994.
377. Li, C., Dai, R. M., Chen, E., and Longo, D. L., Phosphorylation of NF-κB p50 is involved in NF-κB activation and stable DNA binding, J. Biol. Chem., 269, 30089-30092, 1994.
378. Naumann, M. and Scheidereit, C., Activation of NF-κB in vivo is regulated by multiple phosphorylation, EMBO J., 13, 4597-1507, 1994,
379. Heukel, T., Matchleidt, T., Alkalay, I., Krouke, M., Benneriah, Y., and Beauerle, P. A., Rapid proteolysis of IκBα is neccesary for activation of transcription factor NF-κB, Nature, 365, 182-185, 1993.
380. Naumann, M., Wulezyn F. G., and Scheide, T. C., The NF-κB precursos p105 and the protooncogene product Bcl-3 are IκB molecules and control nuclear translocation of NF-κB, EMBO J., 12, 213-222, 1993.
381. Kumar, A., Haque, J., Lacoste, J., Hiscott, J., and Williams, B., Double-stranded RNA-dependent protein kinase activates transcription factor NF-κB by phosphorylating IκB, Proc. Natl. Acad. Sci. U.S.A., 91, 6228-6232, 1994.
382. Lis, S. and Sedivy, J., Raf protein kinase activates the NF-κB transcription factor by dissociating the cytoplasmic NF-κB-IκB complex, Proc. Natl. Acad. Sci. U.S.A, 90, 9247-9251, 1993.
383. Finco, T. and Baldwin, A., QκB site-dependent induction of gene expression by diverse inducers of NF-κB requires Raf-1, J. Biol. Chem., 268, 676-679, 1993.
384. Genot, E. M., Parker, P. J., and Cantrell, D. A., Analysis of the role of PKC alpha, epsilon and zeta in T cell activation, J. Biol. Chem., 270, 9833-9838, 1995.
385. Diaz-Meco, M. T., Dominguez, Y., Sanz, Y., Dent, P., Lozano, J., Municio, M., Berra, E., Hay, R., Sturgill, T., and Moscat, J., PKCζ induces phosphorylation mid inactivation of IκB in vitro, EMBO J., 13, 2842-2848, 1994.
386. DiDanto, J. A., Hayakawa, M., Rothwarf, D. M., Zandi, E., and Karin, M., A cytokine-responsive IκB kinase that activates the transcription NF-κB, Nature, 386, 548-551, 1997.
387. Tahanos, D. and Maniatis, T., NF-κB: a lesson in family values, Cell, 80, 529-532, 1995.
388. Lin, B. B., Cross, S. L., Halden, N. F., Roman, D. G., Toledano, M. B., and Leonard, W. J., Delineation of an enhancer like positive regulatory element in the IL-2Rα chain gene, Mol. Cell. Biol., 10, 850-853, 1990.
389. Ballard, D. W., Bohnlein, E., Lowenthal, J. W., Wano, Y., Franza, B. R., and Greene, W. C., HTLV-1 Tax induces cellular proteins that activate the NF-κB element in the IL-2Rα gene, Science, 241, 1652-1659, 1988.
390. Pomerantz, J. L., Mauxion, F., Yoshida, M., Greene, W. C., and Sen, R., A., Second sequence element located 3′ to the NF-κB binding site regulates IL-2Rα gene induction, J. Immunol., 143, 4275-4281, 1989.
391. Toledano, M. B., Roman, D. G., Halden, N. F., Lin, B. B., and Leonard, W. J., The same target sequences are differentially important for the activation of the IL-2Rα gene in two distinct T cell lines, Proc. Natl. Acad. Sci. U.S.A., 87, 1830-1836, 1990.
392. Gómez, J., García-Domingo, C., Martínez-A, C., and Rebollo, A., Role of NF-κB in the control of apoptotic and proliferative responses in IL-2-responsive T cells, Frontiers Biosci., 2, 49-60, 1997.
393. Seu, J., Venbatarmaman, L., Shinbai, Y., Pierce, J. W., Ali, F. W., Buraboff, S. J., and Sen, R., Expression and induction of NF-κB related proteins in thymocytes, J. Immunol., 154, 3213-3218, 1995.
394. Rebollo, A., Mérida, I., Gómez, J., Pitton, C., Silva, A., Martinez, C., and García, A., Differential effect of rapamycin A in proliferation in a murine T cell line expressing either intermediate or high-affinity receptor for IL-2, Cytokine, 7, 277-286, 1995.
395. Bauerle, P. A. and Baltimore, D., NF-κB: ten years after, Cell, 87, 13-20, 1996.
396. Perkins, N. D., Felzien, L. K., Betts, J. C., Leung, K., Beach, D. H., and Nabel, G. J., Regulation of NF-κB by cyclin-dependent kinases associated with the p300 coactivator, Science, 275, 523-527, 1997.
397. Yin, X. M., Oltvai, Z., and Korsmeyer, S. J., BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax, Nature, 369, 321-323, 1994.
398. Jacobson, M. D., Burne, J. F., King, M. P., Miyashita, T., Reed, J. C., and Raff, M. C., Bcl-2 blocks apoptosis in cells lacking mitochondrial DNA, Nature, 361, 365-369, 1993.
399. Krajewski, S., Tanaka, S., Schibler, M. J., Fenton, W., and Reed, J. C., Investigation of the subcellular distribution of the bcl-2 oncoprotein: residence in the nuclear envelope, endoplasmic reticulum, and outer mitochondrial membranes, Cancer Res., 53, 4701-4714, 1993.
400. Tanaka, S., Saito, K., and Reed, J. C., Structure-function analysis of the Bcl-2 oncoprotein. Addition of a heterologous transmembrane domain to portions of the bcl-2 beta protein restores functions as a regulator of cell survival, J. Biol. Chem., 268, 10920-10926, 1993.
401. White, E., Life, death, and the pursuit of apoptosis, Genes Dev., 10, 1-15, 1996.
402. Weller, M., Malpiero, U., Aguzzi, A., Reed, J. C., and Fontana, A., Protooncogene bcl-2 gene transfer abrogates Fas/APO-1 antibody-mediated apoptosis of human malignant glioma cells and confers resistance to chemotherapeutic drugs and therapeutic irradiation, J. Clin. Invest., 85, 2633-2643, 1995.
403. Schwartz, L. M. and Osborne, B. A., Programmed cell death, apoptosis and killer genes, Immunol. Today, 14, 582-590, 1993.
404. Adachi, Y., Oyaizu, N., Than, S., McCloskey, T. W., and Pahwa, S., IL-2 rescues in vitro lymphocyte apoptosis in patients with HIV infection: correlation with its ability to block culture-induced down-modulation of Bcl-2, J. Immunol., 157, 4184-4193, 1996.
405. Akbar, A. N., Borthwick, N. J., Wickremasinghe, R. G., Panayotidis, P., Pilling, D., Bofill, M., Krajewski, S., Reed, J. C., and Salmon, M., Interleukin-2 receptor common gamma-chain signaling cytokines regulates activated T cell apoptosis in response to growth factor withdrawal: selective induction of anti-apoptotic (bcl-2, bcl-xL) but not proapoptotic (bax, bcl-xS) gene expression, Eur. J. Immunol., 26, 294-299, 1996.
406. Korsmeyer, S. J., Yin, X. M., Oltvai, Z. M., Veis-Novack, D. J., and Linette,G. P., Reactive oxygen species and the regulation of cell death by the Bcl-2 gene family, Biochim. Biophys. Acta., 1271, 63-66, 1995.
407. Yang, J., Liu, X., Bhalla, K., Kim, C. N., Ibrado, A. M., Cai, J., Peng, T. I., Jones, D. P., and Wang, X., Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked, Science, 215, 1129-1132, 1997.
408. Kluck, R. M., Bossy-Wetzel, E., Greene, D. R., and Newmeyer, D. D., The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis, Science, 275, 1132-1136, 1997.
409. Chiarugi, V., Magnelli, L., Cinelli, M., and Basi, G., Apoptosis and the cell cycle, Cell. Mol. Biol. Res., 40, 603-612, 1994.
410. Haffner, R. and Oren, M., Biochemical properties and biological effects of p53, Curr. Opin. Genet. Dev., 5, 84-90, 1995.
411. + helper T cells. A model for the long-term survival of memory cells, J. Immunol., 156, 1764-1771, 1996.
412. Deng, G. and Podack, E. R., Suppression of apoptosis in a cytotoxic T-cell line by interleukin 2-mediated gene transcription and deregulated expression of the protooncogene bcl-2, Proc. Natl. Acad. Sci. U.S.A., 90, 2189-2193, 1993.
413. Rao, L. and White, E., Bcl-2 and the ICA family of apoptotic regulators: making a connection, Curr. Opin. Genet. Dev., 7, 52-58, 1997.
414. Huang, D. C. S., O'Reilly, L. A., Strasser, A., Cory, S., The anti-apoptosis function of Bcl-2 can be genetically separated from its inhibitory effect on cell cycle entry, EMBO J., 16, 4628-4638, 1997.
415. Wang, H-G., Rapp, U. R., and Reed, J. C., Bcl-2 targets the protein kinase Raf-1 to mitochondria, Cell, 87, 629-638, 1996.
416. Park, J., Kim, Y., Oh, J. Y., Lee, K., Han, P-L., and Choi, E-J., Activation of c-jun N-terminal kinase antagonizes an antiapoptotic action of Bcl-2, J. Biol. Chem., 272, 16725-16728, 1997.
417. Henriksson, M. and Luscher, B., The c-myc network: essential regulators of cell growth and differentiation, Adv. Cancer Res., 109-182, 1996.
418. Ryan, K. M. and Birnie, G. D., Myc oncogenes: the enigmatic family, Biochem. J., 314, 713-721, 1996.
419. Evan, G., Wyllie, A. H., Gilbert, C., Littlewood, T., Land, H., Brooks, M., Waters, C., Penn, L., and Hancock, D., Induction of apoptosis in fibroblasts by c-myc protein, Cell, 69, 119-128, 1992.
420. Amati, B., Littlewood, T., Evan, G., and Land, H., The c-myc protein induces cell cycle progression and apoptosis through dimerization with Max, EMBO J., 12, 5083-5087, 1993.
421. Amati, B. and Land, H., Myc-Max-Mad: a transcription factor network controlling cell cycle progression, differentiation and death, Curr. Opin. Genet. Dev., 4, 102-108, 1994.
422. Cole, M. D., The myc oncogene: its role in transformation and differentiation, Anu. Rev. Genet., 20, 361-384, 1986.
423. Blackwood, E. M. and Eisenman, R. N., Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with myc, Science, 251, 1211-1217, 1991.
424. Prendergast, G. C., Lawe, D., and Ziff, E. B., Association of Myn, the murine homolog of Max, with c-myc stimulates methylation-sensitive DNA binding and Ras cotransformation, Cell, 65, 395-407, 1991.
425. Packham, G. and Cleveland, J. L., C-myc and apoptosis, Biochim. Biophys. Acta, 1242, 11-28, 1995.
426. cdc2 and cyclin-dependent kinase-2 in T lymphocites, J. Immunol., 152, 4328-4335, 1994.
427. Spotts, G. D., Patel, S. V., Xiao, Q., and Hann, S. R., Identification of downstream-initiated c-myc proteins which are dominant-negative inhibitors of transacti- vation by fully-length c-myc proteins, Mol. Cell. Biol., 17, 1459-1468, 1997.
428. Asao, H., Tanaka, N., Ishii, N., Higuchi, M., Takeshita, T., Nakamura, M., Shirasawa, T., and Sugamura, K., Interleukin 2-induced activation of JAK3: possible involvement in signal transduction for c-myc induction and cell proliferation, FEBS Lett., 351, 201-206, 1994.
429. Kawahara, A., Minami, Y., Miyazaki, T., Ihle, J. N., and Taniguchi, T., Critical role of the interleukin 2 (IL-2) receptor γ-chain-associated Jak3 in the IL-2-induced c-fos and c-myc, but not bcl-2, gene induction, Proc. Natl. Acad. Sci. U.S.A., 92, 8724-8728, 1995.
430. Lerga, A., Belandia, B., Delgado M. D., Cuadrado, M. A., Richard, C., Ortiz, J. M., Martín-Pérez, J., and León, J., Down-regulation of c-myc and max genes is associated to inhibition of protein phosphatase 2A in K562 human leukemia cells, Biol. Biophys. Res. Commun., 215, 889-895, 1995.
431. Wyllie, A. H., The genetic regulation of apoptosis, Curr. Opin. Genet. Dev., 5, 97-104, 1995.
432. Rahmsdorf, H. J., Jun: transcription factor and oncoprotein, J. Mol. Med., 74, 725-747, 1996.
433. Karin, M., Liu, Zg., and Zandi, E., AP-1 function and regulation, Curr. Opin. Cell. Biol., 9, 240-246, 1997.
434. Chen, J., Stewart, V., Spyrou, G., Hilberg, F., Wagner, E. F., and Alt, F. W., Generation of normal T and B lymphocytes by c-jun-deficient embryonic stem cells, Immunity, 1, 65-72, 1994.
435. Jain, J., Nalefski, E. A., McCaffrey, P. G., Johnson, R. S., Spiegelman, B. M., Papaioannou, V., and Rao, A., Normal peripheral T-cell function in c-Fos-deficient mice, Mol. Cell. Biol., 14, 1566-1574, 1994.
436. Treisman, R., Journey to the surface of the cell: Fos regulation and the SRE, EMBO J., 14, 4905-4913, 1995.
437. Murai, H., Ikeda, M., Kishida, S., Ishida, O., Okazaki-Kishida, M., Matsuura, Y., and Kikuchi, A., Characterization of Ral GDP dissociation stimulator-like (RGL) activities to regulate c-fos promoter and the GDP/GTP exchange of Ral, J. Biol. Chem., 272, 10483-10490, 1997.
438. Preston, G. A., Lyon, T. T., Yin, Y., Lang, J. E., Solomon, G., Annab, L., Srinivasan, D. G., Alcorta, D. A., and Barrett, J. C., Induction of apoptosis by c-Fos protein, Mol. Cell. Biol., 16, 211-218, 1996.
439. Bossy-Wetzel, E., Bakiri, L., and Yaniv, M., Induction of apoptosis by the transcription factor c-Jun, EMBO J., 16, 1695-1709, 1997.
440. Mils, V., Piette, J., Barette, C., Veyrune, J., Tesniere, A., Escot, C., Guilhou, J. J., and Basset-Seguin, N., The protooncogene c-fos increases the sensitivity of keratinocytes to apoptosis, Oncogene, 14, 1555-1561, 1997.
441. Gajate, C., Alonso, M. T., Schimmang, T., and Mollinedo, F., C-Fos is not essential for apoptosis, Biochem. Biophys. Res. Commun., 218, 267-272, 1996.
442. Roffler-Tarlov, S., Brown, J. J., Tarlov, E., Stolarov, J., Chapman, D. L., Alexiou, M., and Papaioannou, V. E., Programmed cell death in the absence of c-Fos and c-Jun, Development, 122, 1-9, 1996.
443. Rebollo, A., Gómez, J., and Martínez-A, C., Lessons from immunological, biochemical and molecular pathways of the activation mediated by IL-2 and IL-4, Adv. Immunol., 63, 127-196, 1996.
444. Satoh, T., Nakafuku, M., Miyajima, A., and Kaziro, Y., Involvement of ras p21 protein in signal-transduction pathways from interleukin 2, interleukin 3, and granulocyte/macrophage colony-stimulating factor, but not from interleukin 4, Proc. Natl. Acad. Sci. U.S.A., 88, 3314-3318, 1991.