Integration of positive and negative growth signals during ras pathway activation in vivo

Current Opinion in Genetics and Development

Volumn 10, Issue 1, 2000, Pages 106-113

  Frame, Sheelagh ^a   Balmain, Allan ^b  

^a UNIVERSITY OF DUNDEE   (United Kingdom)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CELL CYCLE PROTEIN; CYCLIN D1; INHIBITOR PROTEIN; RAS PROTEIN;

APOPTOSIS; CARCINOGENESIS; CELL CYCLE; CELL DEATH; CELL DIFFERENTIATION; CELL GROWTH; ONCOGENE RAS; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION;

EID: 0034002461     PISSN: 0959437X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0959-437X(99)00052-0     Document Type: Review

References (76)

1. Paul J. Roles of oncogenes in carcinogenesis. Iverson O.H. Theories of Carcinogenesis. 1986;145-160 Hemisphere Publishing, New York.
2. Leone G., DeGregori J., Sears R., Jakoi L., Nevins J.R. Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F. Nature. 387:1997;422-426.
3. Lloyd A.C., Obermuller F., Staddon S., Barth C.F., McMahon M., Land H. Cooperating oncogenes converge to regulate cyclin/cdk complexes. Genes Dev. 11:1997;663-677.
4. Downward J. Cell cycle: routine role for Ras. Curr Biol. 7:1997;R258-R260.
5. Lloyd A.C. Ras versus cyclin-dependent kinase inhibitors. Curr Opin Genet Dev. 8:1998;43-48.
6. Kauffmann-Zeh A., Rodriguez-Viciana P., Ulrich E., Gilbert C., Coffer P., Downward J., Evan G. Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB. Nature. 385:1997;544-548.
7. Marshall C.J. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 80:1995;179-185.
8. Marshall C.J. Ras effectors. Curr Opin Cell Biol. 8:1996;197-204.
9. White M.A., Nicolette C., Minden A., Polverino A., Van Aelst L., Karin M., Wigler M.H. Multiple Ras functions can contribute to mammalian cell transformation. Cell. 80:1995;533-541.
10. Khosravi-Far R., White M.A., Westwick J.K., Solski P.A., Chrzanowska-Wodnicka M., Van Aelst L., Wigler M.H., Der C.J. Oncogenic Ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation. Mol Cell Biol. 16:1996;3923-3933.
11. Yang J.J., Kang J.S., Krauss R.S. Ras signals to the cell cycle machinery via multiple pathways to induce anchorage independent growth. Mol Cell Biol. 18:1998;2586-2595.
12. Downward J. Ras signalling and apoptosis. Curr Opin Genet Dev. 8:1998;49-54.
13. Adler V., Pincus M.R., Brandt-Rauf P.W., Ronai Z. Complexes of p21RAS with JUN N-terminal kinase and JUN proteins. Proc Natl Acad Sci USA. 92:1995;10585-10589.
14. Russell M., Lange-Carter C.A., Johnson G.L. Direct interaction between Ras and the kinase domain of mitogen-activated protein kinase kinase kinase (MEKK1). J Biol Chem. 270:1995;11757-11760.
15. Rausch O., Marshall C.J. Tyrosine 763 of the murine granulocyte colony-stimulating factor receptor mediates Ras-dependent activation of the JNK/SAPK mitogen- activated protein kinase pathway. Mol Cell Biol. 17:1997;1170-1179.
16. Khwaja A., Rodriguez-Viciana P., Wennstrom S., Warne P.H., Downward J. Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J. 16:1997;2783-2793.
17. Pap M., Cooper G.M. Role of glycogen synthase kinase-3 in the phosphatidylinositol 3- Kinase/Akt cell survival pathway. J Biol Chem. 273:1998;19929-19932.
18. del Peso L., Gonzalez-Garcia M., Page C., Herrera R., Nunez G. Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science. 278:1997;687-689.
19. ••].
20. ••] demonstrate that PI3K/PKB activation is a necessary part of the link between TNF and IL-1 signalling and NF-κB activation. They show that activation of NF-κB occurs by different routes - PKB phosphorylation of T23 on IKKα in response to TNF, phosphorylation and transactivation of NF-κB following IL-1 stimulation.
21. Pece S., Chiariello M., Murga C., Gutkind J.S. Activation of the protein kinase Akt/PKB by the formation of E-cadherin-mediated cell-cell junctions. Evidence for the association of phosphatidylinositol 3-kinase with the E-cadherin adhesion complex. J Biol Chem. 274:1999;19347-19351. The activation of Akt/PKB following formation of cell-cell contacts in MDCK cells is shown to be mediated by the association and tyrosine phosphorylation of the p85 subunit of PI3K by the E-cadherin adhesion complex. This, along with [16] provides evidence that components in the extracellular environment involved in cell-matrix or cell-cell interactions can initiate the transduction of intracellular signalling pathways to ultimately control epithelial cell fate.
22. Taylor S.J., Shalloway D. Cell cycle-dependent activation of Ras. Curr Biol. 6:1996;1621-1627.
23. Mittnacht S., Paterson H., Olson M.F., Marshall C.J. Ras signalling is required for inactivation of the tumour suppressor pRb cell-cycle control protein. Curr Biol. 7:1997;219-221.
24. Peeper D.S., Upton T.M., Ladha M.H., Neuman E., Zalvide J., Bernards R., DeCaprio J.A., Ewen M.E. Ras signalling linked to the cell-cycle machinery by the retinoblastoma protein. Nature. 386:1997;177-181. [published erratum appears in Nature 1997 386:521].
25. Kaldis P. The cdk-activating kinase (CAK): from yeast to mammals. Cell Mol Life Sci. 55:1999;284-296.
26. Zhang S., Ramsay E.S., Mock B.A. Cdkn2a, the cyclin-dependent kinase inhibitor encoding p16INK4a and p19ARF, is a candidate for the plasmacytoma susceptibility locus, Pctr1. Proc Natl Acad Sci USA. 95:1998;2429-2434.
27. Filmus J., Robles A.I., Shi W., Wong M.J., Colombo L.L., Conti C.J. Induction of cyclin D1 overexpression by activated ras. Oncogene. 9:1994;3627-3633.
28. Serrano M., Lin A.W., McCurrach M.E., Beach D., Lowe S.W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 88:1997;593-602.
29. 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. 15:1995;3654-3663.
30. Gille H., Downward J. Multiple ras effector pathways contribute to G(1) cell cycle progression. J Biol Chem. 274:1999;22033-22040.
31. Diehl J.A., Cheng M., Roussel M.F., Sherr C.J. Glycogen synthase kinase-3β regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 12:1998;3499-3511.
32. Cross D.A., Alessi D.R., Cohen P., Jelkovich M., Hemmings B.A. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 378:1995;785-789.
33. Hashemolhosseini S., Nagamine Y., Morley S.J., Desrivieres S., Mercep L., Ferrari S. Rapamycin inhibition of the G1 to S transition is mediated by effects on cyclin D1 mRNA and protein stability. J Biol Chem. 273:1998;14424-14429.
34. Takuwa N., Fukui Y., Takuwa Y. Cyclin D1 expression mediated by phosphatidylinositol 3-kinase through mTOR-p70(S6K)-independent signaling in growth factor-stimulated NIH 3T3 fibroblasts. Mol Cell Biol. 19:1999;1346-1358.
35. Klippel A., Escobedo M.A., Wachowicz M.S., Apell G., Brown T.W., Giedlin M.A., Kavanaugh W.M., Williams L.T. Activation of phosphatidylinositol 3-kinase is sufficient for cell cycle entry and promotes cellular changes characteristic of oncogenic transformation. Mol Cell Biol. 18:1998;5699-5711.
36. Bi L., Okabe I., Bernard D.J., Wynshaw-Boris A., Nussbaum R.L. Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110α subunit of phosphoinositide 3-kinase. J Biol Chem. 274:1999;10963-10968.
37. Treinies I., Paterson H.F., Hooper S., Wilson R., Marshall C.J. Activated MEK stimulates expression of AP-1 components independently of phosphatidylinositol 3-kinase (PI3-kinase) but requires a PI3-kinase signal to stimulate DNA synthesis. Mol Cell Biol. 19:1999;321-329. This elegant paper demonstrates, using an inducible MEK-ER construct, that stimulation of DNA synthesis by activated MEK can be blocked by PI3K inhibitors. This indicates that PI3K and not MEK is essential for entry into S phase and that activation of PI3K probably occurs, in this system, by autocrine mechanisms.
38. Franza B.R. Jr., Maruyama K., Garrels J.I., Ruley H.E. In vitro establishment is not a sufficient prerequisite for transformation by activated ras oncogenes. Cell. 44:1986;409-418.
39. Hirakawa T., Ruley H.E. Rescue of cells from ras oncogene-induced growth arrest by a second, complementing, oncogene. Proc Natl Acad Sci USA. 85:1988;1519-1523.
40. Ridley A.J., Paterson H.F., Noble M., Land H. Ras-mediated cell cycle arrest is altered by nuclear oncogenes to induce Schwann cell transformation. EMBO J. 7:1988;1635-1645.
41. Bailleul B., Surani M.A., White S., Barton S.C., Brown K., Blessing M., Jorcano J., Balmain A. Skin hyperkeratosis and papilloma formation in transgenic mice expressing a ras oncogene from a suprabasal keratin promoter. Cell. 62:1990;697-708.
42. Missero C., Di Cunto F., Kiyokawa H., Koff A., Dotto G.P. The absence of p21Cip1/WAF1 alters keratinocyte growth and differentiation and promotes ras-tumor progression. Genes Dev. 10:1996;3065-3075.
43. Brown J.P., Wei W., Sedivy J.M. Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. Science. 277:1997;831-834.
44. Pantoja C., Serrano M. Murine fibroblasts lacking p21 undergo senescence and are resistant to transformation by oncogenic Ras. Oncogene. 18:1999;4974-4982.
45. Olson M.F., Paterson H.F., Marshall C.J. Signals from Ras and Rho GTPases interact to regulate expression of p21Waf1/Cip1. Nature. 394:1998;229-295.
46. Takuwa N., Takuwa Y. Ras activity late in G1 phase required for p27kip1 downregulation, passage through the restriction point, and entry into S phase in growth factor-stimulated NIH 3T3 fibroblasts. Mol Cell Biol. 17:1997;5348-5358.
47. Kawada M., Yamagoe S., Murakami Y., Suzuki K., Mizuno S., Uehara Y. Induction of p27Kip1 degradation and anchorage independence by Ras through the MAP kinase signaling pathway. Oncogene. 15:1997;629-637.
48. Alessandrini A., Chiaur D.S., Pagano M. Regulation of the cyclin-dependent kinase inhibitor p27 by degradation and phosphorylation. Leukemia. 11:1997;342-345.
49. Nagahara H., Vocero-Akbani A.M., Snyder E.L., Ho A., Latham D.G., Lissy N.A., Becker-Hapak M., Ezhevsky S.A., Dowdy S.F. Transduction of full-length TAT fusion proteins into mammalian cells: TAT-p27Kip1 induces cell migration. Nat Med. 4:1998;1449-1452.
50. Quintanilla M., Brown K., Ramsden M., Balmain A. Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis. Nature. 322:1986;78-80.
51. Seitz C.S., Lin Q., Deng H., Khavari P.A. Alterations in NF-κB function in transgenic epithelial tissue demonstrate a growth inhibitory role for NF-κB. Proc Natl Acad Sci USA. 95:1998;2307-2312. This paper reported the translocation of NF-κB to the nucleus, as cells migrate from the proliferative basal layer to the non-proliferating, terminal differentiation program of the suprabasal layers, indicating an important role for NF-κB in the switch from proliferation to growth arrest and differentiation in this tissue.
52. van Hogerlinden M., Rozell B.L., Ahrlund-Richter L., Toftgard R. Squamous cell carcinomas and increased apoptosis in skin with inhibited Rel/nuclear factor-kappaB signaling. Cancer Res. 59:1999;3299-3303. Targeted overexpression of a super-repressor form of IκBα in the skin leads to an overall disruption in epidermal homeostasis and hair follicle development as well as an increase in the frequency of apoptosis and the development of squamous cell carcinomas.
53. Mayo M.W., Wang C.Y., Cogswell P.C., Rogers-Graham K.S., Lowe S.W., Der C.J., Baldwin A.S. Jr. Requirement of NF-κB activation to suppress p53-independent apoptosis induced by oncogenic Ras. Science. 278:1997;1812-1815.
54. Finco T.S., Westwick J.K., Norris J.L., Beg A.A., Der C.J., Baldwin A.S. Jr. Oncogenic Ha-Ras-induced, signaling activates NF-κB transcriptional activity, which is required for cellular transformation. J Biol Chem. 272:1997;24113-24116.
55. Bianchi A.B., Fischer S.M., Robles A.I., Rinchik E.M., Conti C.J. Overexpression of cyclin D1 in mouse skin carcinogenesis. Oncogene. 8:1993;1127-1133.
56. Gimenez-Conti I.B., Collet A.M., Lanfranchi H., Itoiz M.E., Luna M., Xu H.J., Hu S.X., Benedict W.F., Conti C.J. p53, Rb, cyclin D1 expression in human oral verrucous carcinomas. Cancer. 78:1996;17-23.
57. Robles A.I., Conti C.J. Early overexpression of cyclin D1 protein in mouse skin carcinogenesis. Carcinogenesis. 16:1995;781-786.
58. Robles A.I., Rodriguez-Puebla M.L., Glick A.B., Trempus C., Hansen L., Sicinski P., Tennant R.W., Weinberg R.A., Yuspa S.H., Conti C.J. Reduced skin tumor development in cyclin D1-deficient mice highlights the oncogenic ras pathway in vivo. Genes Dev. 12:1998;2469-2474.
59. Philipp J., Vo K., Gurley K.E., Seidel K., Kemp C.J. Tumor suppression by p27Kip1 and p21Cip1 during chemically induced skin carcinogenesis. Oncogene. 18:1999;4689-4698. Expression of p27Kip1 is shown to be partially antagonistic to the proliferation of ras-mutated epithelial cells. This paper also demonstrates that in vivo, TPA can down-regulate p27 expression. Thus, this data implies that reduction of p27 levels by TPA in the skin might be causally related to the TPA-induced proliferative effect, reduced differentiation and tumour promotion.
60. Topley G.I., Okuyama R., Gonzales J.G., Conti C., Dotto G.P. p21(WAF1/Cip1) functions as a suppressor of malignant skin tumor formation and a determinant of keratinocyte stem-cell potential. Proc Natl Acad Sci USA. 96:1999;9089-9094.
61. Weinberg W.C., Fernandez-Salas E., Morgan D.L., Shalizi A., Mirosh E., Stanulis E., Deng C., Hennings H., Yuspa S.H. Genetic deletion of p21WAF1 enhances papilloma formation but not malignant conversion in experimental mouse skin carcinogenesis. Cancer Res. 59:1999;2050-2054.
62. Lloyd R.V., Erickson L.A., Jin L., Kulig E., Qian X., Cheville J.C., Scheithauer B.W. p27kip1: a multifunctional cyclin-dependent kinase inhibitor with prognostic significance in human cancers. Am J Pathol. 154:1999;313-323.
63. Chin L., Tam A., Pomerantz J., Wong M., Holash J., Bardeesy N., Shen Q., O'Hagan R., Pantginis J., Zhou H.et al. Essential role for oncogenic Ras in tumour maintenance. Nature. 400:1999;468-472. An exciting study demonstrating that oncogenic ras is required for the genesis and maintenance of melanomas. H-rasV12G is expressed in a regulatable manner in the skin of mice which are null for p16INK4a, thereby allowing the effects of H-ras downregulation to be examined in an in vivo setting. This paper provides encouragement for the prospect of using inhibitors of ras as a valid therapeutic approach.
64. Serrano M., Lee H., Chin L., Cordon-Cardo C., Beach D., DePinho R.A. Role of the INK4a locus in tumor suppression and cell mortality. Cell. 85:1996;27-37.
65. Quelle D.E., Zindy F., Ashmun R.A., Sherr C.J. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell. 83:1995;993-1000.
66. Kemp C.J., Donehower L.A., Bradley A., Balmain A. Reduction of p53 gene dosage does not increase initiation or promotion but enhances malignant progression of chemically induced skin tumors. Cell. 74:1993;813-822.
67. Brown K., Strathdee D., Bryson S., Lambie W., Balmain A. The malignant capacity of skin tumours induced by expression of a mutant H-ras transgene depends on the cell type targeted. Curr Biol. 8:1998;516-524.
68. Aldaz C.M., Trono D., Larcher F., Slaga T.J., Conti C.J. Sequential trisomization of chromosomes 6 and 7 in mouse skin premalignant lesions. Mol Carcin. 2:1989;22-26.
69. Shekhar P.V., Miller F.R. Correlation of differences in modulation of ras expression with metastatic competence of mouse mammary tumor subpopulations. Invasion Metastasis. 14:1994;27-37.
70. Sewing A., Wiseman B., Lloyd A.C., Land H. High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1. Mol Cell Biol. 17:1997;5588-5597.
71. Woods D., Parry D., Cherwinski H., Bosch E., Lees E., McMahon M. Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. Mol Cell Biol. 17:1997;5598-5611.
72. Burns P.A., Kemp C.J., Gannon J.V., Lane D.P., Bremner R., Balmain A. Loss of heterozygosity and mutational alterations of the p53 gene in skin tumours of interspecific hybrid mice. Oncogene. 6:1991;2363-2369.
73. Ruggeri B., Caamano J., Goodrow T., DiRado M., Bianchi A., Trono D., Conti C.J., Klein-Szanto A.J. Alterations of the p53 tumor suppressor gene during mouse skin tumor progression. Cancer Res. 51:1991;6615-6621.
74. Linardopoulos S., Street A.J., Quelle D.E., Parry D., Peters G., Sherr C.J., Balmain A. Deletion and altered regulation of p16INK4a and p15INK4b in undifferentiated mouse skin tumors. Cancer Res. 55:1995;5168-5172.
75. Buchmann A., Ruggeri B., Klein-Szanto A.J., Balmain A. Progression of squamous carcinoma cells to spindle carcinomas of mouse skin is associated with an imbalance of H-ras alleles on chromosome 7. Cancer Res. 51:1991;4097-4101.
76. Vasioukhin V., Degenstein L., Wise B., Fuchs E. The magical touch: genome targeting in epidermal stem cells induced by tamoxifen application to mouse skin. Proc Natl Acad Sci USA. 96:1999;8551-8556. A study which describes an extremely powerful knockout technology which can be used to ablate genes in developing embryonic epidermis or in postnatal skin. The technique utilises tissue-specific promoters in combination with the Cre-Lox and tamoxifen-ER systems to permit regulated expression. This methodology should be extremely useful for the study of various genetic disorders of the skin and is potentially applicable to several other tissues.