Insights into cancer from transgenic mouse models

Journal of Pathology

Volumn 187, Issue 1, 1999, Pages 43-60

  Macleod, Kay F ^a   Jacks, Tyler ^b  

^a UNIVERSITY OF DUNDEE   (United Kingdom)

^b MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

Author keywords

Conditional mutagenesis; Modifier loci; Multi stage tumourigenesis; Oncogene; Targeted mutation; Tumour suppressor gene

Indexed keywords

ANGIOGENESIS; APOPTOSIS; CANCER; CARCINOGENESIS; CELL PROLIFERATION; GENE LOCUS; GENE MUTATION; GENE OVEREXPRESSION; INBREEDING; KNOCKOUT MOUSE; METASTASIS; MUTAGENESIS; ONCOGENE; PHENOTYPE; PRIORITY JOURNAL; RETINOBLASTOMA; REVIEW; STRAIN DIFFERENCE; TRANSGENIC MOUSE; TUMOR SUPPRESSOR GENE;

ANIMALS; CELL TRANSFORMATION, NEOPLASTIC; DISEASE MODELS, ANIMAL; DISEASE PROGRESSION; GENES, P53; MICE; MICE, TRANSGENIC; MUTATION; NEOPLASMS, EXPERIMENTAL;

EID: 0032954092     PISSN: 00223417     EISSN: None     Source Type: Journal    
DOI: 10.1002/(SICI)1096-9896(199901)187:1<43::AID-PATH246>3.0.CO;2-P     Document Type: Review

References (232)

1. Hanahan D. Dissecting multistep tumorigenesis in transgenic mice. Ann Rev Genet 1988; 22: 479-519.
2. Hanahan D. Transgenic mice as probes into complex systems. Science 1989; 246: 1265-1275.
3. Adams JM, Cory S. Transgenic models of tumour development. Science 1991; 254: 1161-1167.
4. Stewart TA, Pattengale K, Leder P. Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion cenes. Cell 1984; 38: 627.
5. Adams JM, Harris AW Pinkert, CA, et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 1985; 318: 533-538.
6. Hanahan D. Heritable formation of pancreatic B-cell tumors in transgenic mice expressing recombinant insulin/simian virus 40 genes. Nature 1985; 315: 115-122.
7. Marshall CJ. Tumor suppressor genes. Cell 1991; 64: 313-326.
8. Knudson AG. Antioncogenes and human cancer. Proc Natl Acad Sci USA 1993; 90: 10914-10921.
9. Jacks T. Tumor suppressor gene mutations in mice. Annu Rev Genet 1996; 30: 630-636.
10. Jacks T, Fazeli A, Schmidt E, et al. Effects of an Rb mutation in the mouse. Nature 1992; 359: 295-300.
11. Lee EY-HP, Chang C-Y, Hu N, et al. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 1992; 359: 288-295.
12. Clarke AR, Maandag ER, van Roon M, et al. Requirement for a functional Rb-1 gene in murine development. Nature 1992; 359: 328-330.
13. Harlow E. For our eyes only. Nature 1992; 359: 270-271.
14. Donehower LA, Harvey M, Slagle BL, et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 1992; 356: 215-221.
15. Jacks T, Remington L, Williams BO, et al. Tumor spectrum analysis in p53-mutant mice. Curr Biol 1994; 4: 1-7.
16. Purdie CA, Harrison DJ, Peter A, et al. Tumour incidence, spectrum and ploidy in mice with a large deletion in the p53 gene. Oncogene 1994; 9: 603-609.
17. Brannan CI, Perkins AS, Vogel KS, et al. Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes Dev 1994; 8: 1019-1029.
18. Jacks T, Shih TS, Schmitt EM, et al. Tumourigenic and developmental consequences of a targeted Nf1 mutation in the mouse. Nature Genet 1994; 3: 353-361.
19. Hakem R, de la Pompa JL, Sirard C, et al. The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse. Cell 1996; 85: 1009-1023.
20. Ludwig T, Chapman DL, Papaioannou E, Efstratiadis A. Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53 and Brca2/p53 nullizygous embryos. Genes Dev 1997; 11: 1226-1241.
21. Serrano M, Lee HW, Chin L., Role of the INK4a locus in tumor suppression and cell mortality. Cell 1996; 85: 27-37.
22. Kamijo T, Zindy F, Roussel MF, et al. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 1997; 91: 649-659.
23. McClatchey AI, Jacks T. Tumor suppressor mutations in mice: the next generation. Curr Opin Genet Dev 1998; 8: 304-310.
24. McClatchey AI, Saotome I, Mercer K, et al. Mice heterozygous for a mutation at the Nf2 tumor suppressor locus develop a range of highly metastatic tumors. Genes Dev 1998; 12: 1121-1133.
25. Shoemaker AR, Gould KA, Luongo C, Moser AR, Dove WF. Studies of neoplasia in the Min mouse. Biochim Biophys Ann 1997; 1332: F25-F48.
26. Vogelstein B, Kinzler KW. The multistep nature of cancer. Trends Genet 1993; 9: 138-141.
27. Kinzler K, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996; 87: 159-170.
28. Christofori G, Naik P, Hanahan D. A second signal supplied by insulin-like growth factor II in oncogene-induced tumorigenesis. Nature 1994; 369: 414-418.
29. Naik P, Karrim J, Hanahan D. The rise and fall of apoptosis during multi-stage tumorigenesis: down-modulation contributes to tumor progression from angiogenic progenitors. Genes Dev 1996; 10: 2105-2116.
30. Perl AK, Wilgenbus P, Dahl U, Semb H, Christofori G. A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature 1998; 392: 190-193.
31. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996; 86: 353-364.
32. Parangi S, Dietrich W, Christofori G, Lander ES, Hanahan D. Tumor suppressor loci on mouse chromosomes 9 and 6 are lost at distinct stages of tumorigenesis in a transgenic model of islet cell carcinoma. Cancer Res 1995; 55: 6071-6076.
33. Umbas R, Isaacs WB, Bringuer PP, et al. Decreased E-cadherin expression is associated with poor prognosis in patients with prostate cancer. Cancer Res 1994; 54: 3929.
34. Vleminckx K, Vakaet L, Mareel M, Fiers W, Van Roy F. Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 1991; 66: 107-119.
35. Takeichi M. Cadherins in cancer: implications for invasion and metastasis. Curr Opin Cell Biol 1993; 5: 806-811.
36. Guilford P, Hopkins J, Harraway J, et al. E-cadherin germline mutations in familial gastric cancer. Nature 1998; 392: 402-405.
37. Balmain A, Ramsden M, Bowden GT, Smith J. Activation of the mouse cellular Harvey Ras gene in chemically induced benign skin papillomas. Nature 1984; 307: 658-660.
38. Bianchi AB, Fischer SM, Robles AI, Rinchik EM, Conti CJ. Overexpression of cyclin D1 in mouse skin carcinogenesis. Oncogene 1993; 8: 1127-1133.
39. Robles AI, Larcher F, Whalin RB, et al. Expression of cyclin D1 in epithelial tissues of transgenic mice results in epidermal hyperproliferation and severe thymic hyperplasia. Proc Natl Acad Sci USA 1996; 93: 7634-7638.
40. Robles AI, Rodriguez-Puebla ML, Glick AB, et al. Reduced skin tumor development in cyclin D1 deficient mice highlights the oncogenic ras pathway in vivo. Genes Dev 1998; 12: 2469-2474.
41. Kemp CJ, Donehower LA, 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 1993; 74: 813-822.
42. Cui W, Fowlis DJ, Bryson S. et al. TGFB1 inhibits the formation of benign skin tumors but enhances progression to invasive spindle carcinomas in transgenic mice. Cell 1996; 86: 531-542.
43. Glick AB, Lee MM, Darwiche N, et al. Targeted deletion of the TGF-B1 gene causes rapid progression to squamous cell carcinoma. Genes Dev 1994; 8: 2429-2440.
44. Cano A, Gamalla C, Kemp CJ, et al. The expression of the cell adhesion molecules E-cadherin, P-cadherin and a6b4 integrin is altered in prermalignant skin tumors in p53 deficient mice. Eur J Cancer 1996; 65: 254-262.
45. Lacey M, Alpert S, Hanahan D. The bovine papillomavirus genome elicits skin tumors in transgenic mice. Nature 1986; 322: 609-612.
46. Arbeit J, Munger K, Howley P, Hanahan D. Progressive squamous epithelial neoplasia in K14-HPV16 transgenic mice. J Virol 1996; 68: 4358-4368.
47. Windle JJ, Albert DA, O'Brien JM, et al. Retinoblastoma in transgenic mice. Nature 1990; 343: 665-668.
48. Williams BO, Remington L, Bronson RT, et al. Cooperative tumorigenic effects of germline mutations in Rb and p53. Nature Genet 1994; 7: 480-484.
49. Vaux DL, Cory S, Adams J. Bcl-2 gene promotes hematopoietic cell survival and cooperates with c-myc to immortalise pre-B cells. Nature 1988; 335: 440-442.
50. Haupt Y, Alexander WS, Barri G, Klinken SP, Adams JM. Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in Eu-Myc transgenic mice. Cell 1991; 65: 753-763.
51. Draper GJ, Sanders BM, Kingston JE. Second primary neoplasms in patients with retinoblastoma. Br J Cancer 1986; 53: 661-671.
52. Friend SH, Horowitz JM, Gerber MR, et al. Deletions of a DNA sequence in retinoblastomas and mesenchymal tumors: organization of the sequence and its encoded protein. Proc Natl Acad Sci USA 1987; 84: 9059-9063.
53. Howes KA, Ransom N, Papermaster DS, et al. Apoptosis or retinoblastoma: alternative fates of photoreceptors expressing the HPV-16 E7 gene in the presence or absence of p53. Genes Dev 1994; 8: 1300-1310.
54. Lee MH, Williams BO, Mulligan G, et al. Targeted disruption of p107: functional overlap between p107 and Rb. Genes Dev 1996; 10: 1621-1632.
55. Robanus-Maandag EC, van der Valk M, Vlaar M, et al. Developmental rescue of an embryonic-lethal mutation in the retinoblastoma gene in chimeric mice. EMBO J 1994; 13: 4260-4268.
56. Robanus-Maandag EC, Dekker M, van der Valk M, et al. p107 is a suppressor of retinoblasloma development in Rb-deficient mice. Genes Dev 1998; 12: 1599-1609.
57. Nigro JM, Baker SJ, Preisinger AC, et al. Mutations in the p53 gene occur in diverse human tumour types. Nature 1989; 342: 705-708.
58. Hollstein M, Sidranksy D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science 1991; 253: 49-53.
59. Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 1994; 54: 4855-4878.
60. Baker SJ, Fearon ER, Nigro JM, et al. Chromosome 17 deletions and p53 gene mutations in colorectal carcinoma. Science 1989; 244: 217-221.
61. Baker SJ, Markowitz S, Fearon ER, Willson JKV, Vogelstein B. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 1990; 249: 912-915.
62. Malkin D, Li FP, Strong C, et al. Germline p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 1990; 250: 1233-1238.
63. Malkin D. p53 and the Li-Fraumeni syndrome. Cancer Genet Cytogenet 1993; 66: 83-92.
64. Lavigueur AL, Maltby V, Mock D, et al. High incidence of lung, bone, and lymphoid tumors in transgenic mice mutant alleles of the p53 oncogenes. Mol Cell Biol 1989; 9: 3982-3991.
65. Kaghad M, Bonnet H, Yang A, et al. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 1997; 90: 809-819.
66. Schmale H, Bamberger C. A novel protein with strong homology to the tumor suppressor p53. Oncogene 1997; 15: 1363-1367.
67. Jost CA, Marin MC, Kaelin WG. p73 is a human p53-related protein that can induce apoptosis. Nature 1997; 389: 191-194.
68. MacCallum DE, Hupp TR, Midgeley CA, et al. The p53 response to ionising radiation in adult and developing murine tissues. Oncocene 1996; 13: 2575-2587.
69. Komarova EA, Chernov M, Franks R, et al. Transgenic mice with p53-responsive lacZ: p53 activity varies dramatically during normal development and determines radiation and drug sensitivity in vivo. EMBO J 1997; 16: 1391-1400.
70. Gottlieb E, Haffner R, King A, et al. Transgenic mouse model for studying the transcriptional activity of the p53 protein: age-and tissue-dependent changes in radiation-induced activation during embryogenesis. EMBO J 1997; 16: 1381-1390.
71. Midgley CA, Owens B, Briscoe CV, et al. Coupling between gamma irradiation, p53 induction and the apoptotic response depends upon cell type in vivo. J. Cell Sci 1995; 108: 1843-1848.
72. Macleod KF, Sherry N, Hannon G, et al. p53-dependent and independent expression of p21 during cell growth, differentiation and DNA damage. Genes Dev 1995; 9: 935-944.
73. Lane DP. p53. guardian of the genome. Nature 1992; 358: 15-16.
74. Lowe SW, Schmitt ES, Smith SW, Osborne BA, Jacks T. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 1993; 362: 847-849.
75. Clarke AR, Purdie CA, Harrison DJ, et al. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 1993; 362: 849-852.
76. Pavletich NP, Chambers KA, Pabo CO. The DNA-binding domain of p53 contains four conserved regions and the major mutation hot spots. Genes Dev 1993; 7: 2556-2564.
77. Harvey M, Vogel H, Morris D, et al. A mutant p5.3 transgene accelerates tumor development in heterozygous but not nullizygous p53-deficient mice. Nature Genet 1995; 9: 305-311.
78. Bowman T, Symonds H, Gu L, et al. Tissue-specific inactivation of p53 tumor suppression in the mouse. Genes Dev 1996; 10: 826-835.
79. Sah VP, Attardi LD, Mulligan G, et al. A subset of p53-deficient embryos exhibit exencephaly. Nature Genet 1995; 19: 175-180.
80. Jones SN, Roe LA, Donehower LA, Bradley A. Rescue of embryonic lethality in mdm2 deficient mice by absence of p53. Nature 1995; 378: 206-206.
81. Montes de Oca Luna R, Wagner DS, Lozano G. Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 1995; 378: 203-206.
82. Nakamura T, Pichel JG, Williams-Simon L, Westphal H. An apoptotic defect in lens differentiation caused by human p5.3 is rescued by a mutant allele. Proc Natl Acad Sci USA 1995; 92: 6142-6146.
83. Godley LA, Kopp JB, Eckhaus M, et al. Wild-type p53 transgenic mice exhibit altered differentiation of the uteric bud and possess small kidneys. Genes Dev 1996; 10: 836-850.
84. Kubbutat MHG, Jones SN, Vousden KH. Regulation of p53 stability by mdm2. Nature 1997; 387: 299-303.
85. Haupt Y, Maya R, Kazaz A. Mdm2 promotes the rapid degradation of p53. Nature 1997; 387: 296-299.
86. Wang XW, Yeh H, Schaeffer L, et al. Modulation of TFIIH-associated nucleotide excision repair activity. Nature Genet 1995; 9: 188-195.
87. Mummenbrauer T, et al. p53 protein exhibits 3′ and 5′ exonuclease activity. Cell 1996; 85: 1089-1099.
88. Ko LJ, Prives C. p53: puzzle and paradigm. Genea Dev 1996; 10: 1054-1072.
89. Levine AJ. p53. the cellular gatekeeper for growth and division. Cell 1997; 88: 323-331.
90. Kern SE, Kinzler KW, Bruskin A, et al. Identification of p53 as a sequence-specific DNA binding protein. Science 1991; 252: 1708-1711.
91. Hupp TR, Meek DW, Midgley CA, Lane DP. Regulation of the specific DNA binding function of p53. Cell 1992; 71: 875-886.
92. Ruyeroft L, Wu J, Lozano G. Transcriptional activation by wild-type but not transforming mutants of the p53 anti-oncogene. Science 1990; 249: 1049-1051.
93. Fields S, Jang SK. Presence of a potent transcription activating sequence in the p53 protein. Science 1990; 249: 1046-1049.
94. Kuerbitz SJ, Plunkett BS, Walsh WV, Kastan MB. Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci USA 1992; 89: 7491-7495.
95. Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW. Participation of p53 protein in the cellular response to DNA damage. Cancer Res 1991; 51: 6304-6311.
96. Kastan M, Zhan Q, El-Deiry WS, et al. A mammalian cell cycle check-point pathway utilising p53 and GADD45 is defective in ataxia-telangiectasia. Cell 1992; 71: 587-597.
97. Lu N, Lane DP. Differential induction of transcriptionally active p53 following UV or ionizing radiation: defects in chromosome instability syndromes? Cell 1993; 75: 765-778.
98. Fritsche M, Haessler C, Brandner G. Induction of nuclear accumulation of the tumor-suppressor protein p53 by DNA damaging agents. Oncogene 1993; 8: 307-318.
99. Canman CE, Gilmer TM, Coutts SB, Kastan MB. Growth factor modulation of p53-mediated growth arrest versus apoptosis. Genes Dev 1995; 9: 600-611.
100. Pietenpol JA, Tokino T, Thiagalingam S, et al. Sequence-specific transcriptional activation is essential for growth suppression by p53. Proc Natl Acad Sci USA 1994; 91: 1998-2002.
101. El-Deiry WS, Tokino T, Velculescu VE, et al. WAF1, a potential mediator of p53 tumor suppression. Cell 1993; 75: 817-825.
102. El-Deiry WS, Harper JW, O'Connor PM, et al. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res 1994; 54: 1169-1174.
103. Xiong Y, Hannon GJ, Zhang H, et al. p21 is a universal inhibitor of cyclin kinases. Nature 1993; 366: 701-704.
104. Brugarolas J, Chandrasekaran C, Gordon JI, et al. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 1995; 377: 552-557.
105. Deng C, Zhang P, Harper JW, Elledge SJ, Leder P. Mice lacking p21 undergo normal development, but are defective in G1 checkpoint control. Cell 1995; 82: 675-684.
106. Yin Y, Tainksy MA, Bischoff KZ, Strong LC, Wahl GM. Wild-type p53 restores cells cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cell 1992; 70: 937-948.
107. Livingstone LR, White A, Sprouse J, et al. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell 1992; 70: 923-935.
108. Cross SM, et al. A p53-dependent mouse spindle checkpoint. Science 1995; 267: 1353-1356.
109. Fukasawa K, Choi T, Kuriyama R, Rulong S, Vande Woude GF. Abnormal centrosome amplification in the absence of p53. Science 1996; 271: 1744-1747.
110. Rowan S, Ludwig RL, Haupt Y, et al. Specific loss of apoptotic but not cell-cycle arrest function in a human tumor derived p53 mutant. EMBO J 1996; 15: 827-838.
111. Symonds H, Krall L, Remington L, et al. p53-dependent apoptosis suppresses tumor growth and progression in vivo. Cell 1994; 78: 703-711.
112. Pan H, Griep A. Altered cell cycle regulation in the lens of HPV-16 E6 or E7 transgenic mice: implications for tumor suppressor gene function in development. Genes Dev 1994; 8: 1285-1299.
113. Sabbatini P, Lin J, Levine AJ, White E. Essential role for the p53-mediated transcription in E1A-induced apoptosis. Genes Dev 1995; 9: 2184-2192.
114. Attardi L, Lowe SW, Brugarolas J, Jacks T. Transcriptional activation by p53, but not induction of the p21 gene is essential for oncogene-mediated apoplosis. EMBO J 1996; 15: 3693-3701.
115. Polyak K, Xia Y, Zweier JL, Kinzler K, Vogelstein B. A model for p53-induced apoptosis. Nature 1997; 389: 300-305.
116. Caelles C, Helmberg A, Karin M. p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes. Nature 1994; 370: 220-223.
117. Haupt Y, Rowan S, Shaulian E, Vousden K, Oren M. Induction of apoptosis in HeLa cells by trans-activation-deficient p53. Genes Dev 1995; 9: 2170-2183.
118. Ludwig RL, Bates S, Vousden KH. Differential activation of target cellular promoters by p53 mutants with impaired apoptotic function. Mol Cell Biol 1996; 16: 4952-4960.
119. Friedlander P, Haupt Y, Prives C, Oren M. A mutant p53 that discriminates between p53-responsive genes cannot induce apoptosis. Mol Cell Biol 1996; 16: 4961-4971.
120. Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 1995; 80: 293-299.
121. Buckbinder L, Talbott R, Velasco-Miguel S, et al. Induction of the growth inhibitor IGF-binding protein 3 by p53. Nature 1995; 377: 646-649.
122. Knudson CM, Tung KKK, Tourtellotte WG, Brown GA, Korsmeyer SJ. Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science 1995; 270: 96-99.
123. Yin C, Knudson CM, Korsmeyer SJ, Van Dyke T. Bax suppresses tumorigenesis and stimulates apoptosis in vivo. Nature 1997; 385: 637-640.
124. Guidos CJ, Williams CJ, Grandal I, et al. V(D)J recombination activates a p53-dependent DNA damage checkpoint in seid lymphocyte precursors. Genes Dev 1996; 10: 2038-2054.
125. Nacht M, Strasser A, Chan YR, et al. Mutations in the p53 and SCID genes cooperate in tumorigenesis. Genes Dev 1996; 10: 2055-2066.
126. Bosnia M. Carroll A. The scid mouse mutant: definition, characterisation, and potential uses. Annu Rev Immunol 1991; 9: 323-350.
127. Blunt T, Finnie NJ, Taccioli GE, et al. Defective DNA-dependent protein kinase activity is linked to V(D)J recombination and DNA repair defects associated with the murine seid mutation. Cell 1995; 80: 813-823.
128. Kirschgessner CU, Paul CK, Evans JW, et al. DNA-dependent kinase (p350) as a candidate gene for the murine seid defect. Science 1995; 267: 1178-1182.
129. Peterson SR, Kurimasa A, Oshimura M, et al. Loss of catalytic sub-unit of the DNA-dependent protein kinase in DNA double-strand break repair mutant mammalian cells. Proc Natl Acad Sci USA 1995; 92: 3171-3174.
130. Shieh S, Ikeda M, Taya Y, Prives C. DNA damage-induced phosphorylation of p53 alleviates inhibition by mdm-2. Cell 1997; 91: 325-334.
131. Rabbitts TH. Chromosomal translocations in human cancers. Nature 1994; 372: 143-149.
132. Liao MJ, Mill MJ, Zhang X, et al. No requirement for V(D)J recombination in p53-deficient thymic lymphoma. Mol Cell Biol 1998; 18: 3495-3501.
133. Nacht M, Jacks T. V(D)J recombination is not required for the development of lymphoma in p53-deficient mice. Cell Growth Diff 1998; 9: 131-138.
134. Knudson AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971; 68: 820-823.
135. Venkatachalam S, Shi Y, Jones SN, et al. Retention of wild-type p53 in tumors from p53 heterozygous mice: reduction of p53 dosage can promote cancer formation. EMBO J 1998; 17: 4657-4667.
136. Wang Y, Schwedes JF, Parks D, Mann K, Tegtmeyer P. Interaction of p53 with its consensus DNA-bindmg site. Mol Cell Biol 1995; 15: 2157-2165.
137. Barak Y, Gottlieb E, Juven-gershon T. Regulation of mdm 2 expression by p53: alternative promoters produce transcripts with non-identical translation potential. Genes Der 1994; 8: 1739-1749.
138. Zauberman A, Lupo A, Oren M. Identification of p53 target genes through immune selection of genomic DNA: the cyclin G gene contains two distinct p53 binding sites. Oncogene 1995; 10: 2361-2366.
139. Ziegler A, Jonason AS, Leffell DJ, et al. Sunburn and p53 in the onset of skin cancer. Nature 1994; 372: 773-776.
140. Thompson TC, Park SH, Timme TL, et al. Loss of p53 function leads to metastasis in ras + myc initiated mouse prostate cancer. Oncogene 1995; 10: 869-879.
141. Graeber TG, Osmanian C, Housman DE, et al. Hypoxia mediated selection of cells with diminished apoptolic potential in solid tumors. Nature 1996; 379: 88-91.
142. Van Meir EG, Polverini PJ, Chazin VR, et al. Release of an inhibitor of angiogenesis upon induction of wild-type p53 expression in glioblastoma cells. Nature Genet 1994; 8: 171-176.
143. Dameron KM, Volpert MA, Tainsky MA, Bouck N. Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 1994; 265: 1582-1584.
144. Lowe SM, Ruley HE, Jacks T, Housman DE. p53-dependent apoplosis modulates the cytoxicity of anticancer agents. Cell 1993; 74: 957-967.
145. Lowe SW, Bodis S, McClatchey A, et al. p53 status and the efficacy of cancer therapy in vivo. Science 1994; 266: 807-810.
146. Land H, Parada LF, Weinberg RA. Tumorigemc conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature 1983; 304: 596-602.
147. Sinn E, Muller W, Patttengale P, et al. Coexpression of MMTV/v-H-ras and MMTV/c-myc genes in transgenic mice: synergistic action of oncogenes in vivo. Cell 1987; 49: 465-475.
148. Langdon WY, Harris AW, Cory S, Adams J. The c-myc oncogene perturbs B lymphocyte development in Eu-myc transgenic mice. Cell 1986; 47: 11-18.
149. Langdon WY, Harris AW, Cory S. Acceleration of B lymphoid tumorigenesis in Eu-myc transgenic mice by v-H-ras and v-raf but not v-abl. Oncogene Res 1989; 4: 253-258.
150. Reed JC. Double identity for proteins of the Bcl-2 family. Nature 1997; 387: 773-776.
151. Tsujimoto Y, Gorham J, Cossman J, Jaffe E, Croce CM. The t(14:18) chromosome translocations involved in B cell neoplasms results from mistakes in V(D)J joining. Science 1985; 229: 1390-1393.
152. Cleary ML, Sklar J. Nucleotide sequence of a t(14:18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint cluster region near a transcriptionally active locus on chromosome 18. Proc Natl Acad Sci USA 1995; 82: 7439-7443.
153. Strasser A, Harris AW, Bath ML, Cory S. Novel primitive lymphoid tumors induced in transgenic mice by cooperation between myc and bcl-2 Nature 1990; 348: 331-333.
154. Evan GI, Wyllie AH, Gilbert CS, et al. Induction of apoptosis in fibroblasts by c-myc protein. Cell 1992; 69: 1083-1093.
155. Evan GI, Brown L, Whyte M, Harrington E. Apoptosis and the cell cycle. Curr Opin Cell Biol 1995; 7: 825-834.
156. Harrington EA, Bennett MR, Fanidi A, Evan GI. c-myc induced apoptosis in fibroblasts is inhibited by specific cytokines. EMBO J 1994; 13: 3286-3295.
157. Hueber A, Evan GI. Traps to catch unwary oncogenes. TIGS 1998; 14: 364-367.
158. van Lohuizen M, Verbeck S, Scheijen B, et al. Identification of cooperating oncogenes in Eu-myc transgenic mice by provirus tagging. Cell 1991; 65: 737-752.
159. Harbour JW, Lai S-L. Whang-Pend J, et al. Abnormalities in structure and expression of the human retinoblastoma gene in SCLC. Science 1988; 241: 353-356.
160. Hensel CH, Hsieh, CL, Gazdar AF, et al. Altered structure and expression of the human retinoblastoma susceptibility gene in small cell lung cancer. Cancer Res 1990; 50: 3067-3072.
161. Horowitz JM, Park SH, Begenmann E, et al. Frequent inactivation of the retinoblastoma anti-oncogene is restricted to a subset of human tumor cells. Proc Natl Acad Sci USA 1990; 87: 2775-2779.
162. Friend SJ, Bernards R, Rogelj S, et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 1986; 323: 643-646.
163. Toguchida J. Ishizaki K, Sasaki MS, et al. Chromosomal reorganisation for the expression of recessive mutation of retinoblastoma susceptibility gene in the development of osteosarconia. Cancer Res 1988; 48: 3939-3943.
164. Lee EY-HP, To J, Shew JY, et al. Inactivation of the retinoblastoma susceptibility gene in human breast cancers. Science 1988; 241: 218-221.
165. Bookstein R, Shew JY, Chen PL, Scully P, Lee WH. Suppression of tumorigenicity of human prostate carcinoma cells by replacing a mutated RB gene. Science 1990; 247: 712-715.
166. Vousden K. Interactions of human papillomavirus transforming proteins with the products of tumor suppressor genes. FASEB J 1993; 7: 872-879.
167. Morgenbesser SD, Williams BO. Jacks T. DePinho RA. p53-dependent apoptosis produced by Rb-deficiency in the developing mouse lens. Nature 1994: 371.
168. Lee EY-HP, Hu N, Yuan S-SF, et al. Dual roles of the retinoblastoma protein in cell cycle regulation and neuron differentiation. Genes Dev 1994; 8: 2008-2021.
169. Macleod K, Hu Y, Jacks T. Loss of Rb activates both p53-dependent and -independent cell death pathways in the developing mouse nervous system. EMBO J 1996; 15:6178-6188.
170. Newbold RF, Overell RW. Fibroblast immortality is a prerequisite for transformation by EJ c-H-Ras oncogene. Nature 1983; 304: 648-651.
171. Lovee H, Sewing A, Lucibello FC, Muller R, Moroy T. Oncogenic activity of cyclin D1 revealed through cooperation with H-ras: link between cell cycle control and malignant transformation. Oncogene 1994; 9: 323-326.
172. Hinds PW, Dowdy SF, Eaton KN, Arnold A. Function of a human cyclin gene as an oncogene. Proc Natl Acad Sci USA 1994; 91: 709-713.
173. Galaktionov K, Lee AK, Eckstein J, et al. cdc25 phosphatases as potential human oncogenes. Science 1995; 269: 1575-1577.
174. Hundley JE. Increased tumor proliferation and genomic instability without decreased apoptosis in MMTV-ras mice deficient for p53. Mol Cell Biol 1997; 17: 723-731.
175. Serrano M, Gomez-Lahoz E, DePinho RA, Beach D, Bar-Sagi D. Inhibition of Ras-induced proliferation and cellular transformation by p16INK4a. Science 1995; 267: 249-252.
176. Tanaka N, Ishihara M, Kitagawa M, et al. Cellular commitment to oncogene induced transformation or apoptosis is dependent on the transcription factor, IRF-1. Cell 1994; 77: 829-839.
177. Chin L. Pomerantz J, Polsky D, et al. Cooperative effects of INK4a and ras in melanoma susceptibility in vivo. Genes Dev 1997; 11: 2822-2834.
178. Pomerantz J, Schreiber-Angus N, Liegois NJ, et al. The Ink4a tumor suppressor gene product p19ARF interacts with mdm2 and neutralises mdm2's inhibition of p53. Cell 1998; 92: 713-723.
179. Zhang Y, Xiong Y. Yarbrough WG. ARF promotes mdm2 degradation and stabilises p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 1998; 92: 725-734.
180. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 1997; 88: 593-602.
181. Luongo C. Moser AR, Gledhill S, Dove WF. Loss of Apc+ in intestinal adenomas from Min mice. Cancer Res 1994; 54: 5947-5952.
182. Zuo L, Weger J, Yang Q, et al. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nature Genet 1996; 12: 97-99.
183. Okamoto A, Demetrick DJ, Spillare EA, et al. Mutations and altered expression of p16INK4a in human cancer. Proc Natl Acad Sci USA 1994; 91: 11045-11049.
184. Wolfel T, Hauer M, Schneider J, et al. A p16INK4a insensitive cdk4 mutant targeted by cytolytic lymphocytes in a human melanoma. Science 1995; 269: 1281-1284.
185. Motokura T, Bloom T, Kim HG, et al. A novel cyclin encoded by a bcl-linked candidate oncogene. Nature 1991; 350: 512-515.
186. Buckley MF, Sweeney KJ, Hamilton, JA, et al. Expression and amplification of cyclin genes in human breast cancer. Oncogene 1993; 8: 2127-2133.
187. Jiang W, Kahn SM, Tomita N, et al. Amplification and expression of the human cyclin D gene in esophageal cancer. Cancer Res 1992; 52: 2980-2983.
188. Weinberg RA. The retinoblastoma protein and cell cycle control. Cell 1995; 81: 323-330.
189. Filed SF, Tsai FY, Kuo F, et al. E2F-1 functions in mice to promote apoptosis and suppress proliferation. Cell 1996; 85: 549-561.
190. Yamasaki L, Jacks T, Bronson R, et al. Tumor induction and tissue atrophy in mice lacking E2F-1. Cell 1996; 85: 537-548.
191. Sicinski P, Donaher JL, Parker SB, et sl. Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 1995; 82; 621-630.
192. Fantl V, Stamp G, Andrews A, Rosewell I, Dickson C. Mice lacking cyclin D1 are small and show defects in eye and mammary gland development. Genes Dev 1995; 9: 2364-2372.
193. Nikitin AY, Lee WH. Early loss of the retinoblastoma gene is associated with impaired growth inhibitor innervation during melanotroph carcinogenesis in Rb+/-mice. Genes Dev 1996; 10: 1870-1879.
194. Zwijsen RML, Wientjens E, Klompmaker R, et al. CDK-independent actuation of estrogen receptor by cyclin D1. Cell 1997; 88: 405-415.
195. Quelle DE, Zindy F, Ashmun RA, Sherr CJ. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 1995; 83: 993-1000.
196. Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell cycle control causing specific inhibition of cyclin D/cdk4. Nature 1993; 366: 704-707.
197. Yamasaki L, Bronson RT, Williams BO, et al. Loss of E2F-1 reduces tumorigenesis and extends the lifespan of Rb1+/-mice. Nature Genet 1998; 18: 360-363.
198. Pierce A, Gimenez-Conti I, Schneider-Broussard R, et al. Increased E2F-1 activity induces skin tumors in mice heterozygous and nullizygous for p53. Proc Natl Acad Sci USA 1998; 95: 8858-8863.
199. Tsai KY, Hu V, Macleod KF, et al. Mutation of E2f-1 suppresses apoptosis and inappropriate S-phase entry and extends survival of Rb-deficient mouse embryos. Mol Cell 1998; 2: 293-304.
200. Festing MFW. Origins and characteristics of inbred strains of mice. Mouse Genome 1993; 91: 393-509.
201. Festing MFW. Inbred strains of mice. Mouse Genome 1994; 92: 373-495.
202. Gariboldi M, Manenti G, Canzian F, et al. Chromosome mapping of murine susceptibility loci to liver carcinogenesis. Cancer Res 1993; 53: 209-211.
203. Gariboldi M, Manenti G, Canzian F, et al. A major susceptibility locus to murine carcinogenesis maps on chromosome 6. Nature Genet 1993; 3: 132-136.
204. Moser AR, Pitot HC, Dove WF. A dominant negative mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 1990; 247: 322-324.
205. Moser AR, Dove WF, Roth KA, Gordon JI. The Min mutation: its effect on gut epithelial cell differentiation and interactions with a modifier system. J Cell Biol 1992; 116: 1517-1526.
206. Su L-K, Kinzler KW, Vogelstein B, et al. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 1992; 256: 668-670.
207. Dietrich WF, Lander ES, Smith JS, et al. Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse. Cell 1993; 75: 631-639.
208. MacPhee M, Chepenik KP, Liddell RA, et al. The secretory phospholipase A2 gene is a candidate for the Mom-1 locus, a major modifier of ApcMin-induced hyperplasia. Cell 1995; 81: 957-966.
209. Kilby NJ, Snaith MR, Murray JAH. Site-specific recombinases: tools for genome engineering. TIGS 1993; 9: 413-421.
210. Kuhn R, Schwenk F, Aguet M, Rajewsky K. Inducible gene targeting in mice. Science 1995; 269: 1427-1429.
211. Gu H, Marth JD, Orban PC, Mossman H, Rajewsky K. Deletion of a DNA polymerase B gone segment in T cells using cell type specific gene targeting. Science 1994; 265: 103-106.
212. Shibata H, Toyama K, Shioya H, et al. Rapid colorectal adenoma formation initiated by conditional targeting of the Ape gene. Science 1997; 278: 120-123.
213. Gossen M, Bonin AL, Freundlieb S, Bujard H. Inducible gene expression systems for higher eukaryotic cells. Curr Opin Biotechnol 1994; 5: 516-520.
214. Feil R, Brocard J, Mascrez B, et al. Ligand-activated site-specific recombination in mice. Proc Natl Acad Sci USA 1996; 93: 10887-10890.
215. Williams BO, Schmitt EM., Remington L, et al. Extensive contribution of Rb-deficient cells to adult chimeric mice with limited histopathological consequences. EMBO J 1994; 13: 4251-4259.
216. Zambrowicz BP, Imamoto A, Fiering S, et al. Disruption of overlapping transcripts in the ROSA Bgeo 26 gene trap strain leads to widespread expression
217. Chen J, Lansford R, Stewart V, Young F, Alt FW. RAG-2-deficient blastocyst complementation; an assay of gene function in lymphocyte development. Proc Natl Acad Sci USA 1993; 90: 4528-4532.
218. Fero ML, Rivkin M, Tasch M, et al. A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis and female sterility in p27Kip1 deficient mice. Cell 1996; 85: 733-744.
219. Kreidberg JA, Sariola H, Loring JM, et al. WT-1 is required for early kidney development. Cell 1993; 74: 679-691.
220. Fodde R, Edelman W, Yang K, van Leeuwen C, Carlson C, A targeted chain termination in the mouse Apc gene results in multiple intestinal tumors. Proc Natl Acad Sci USA 1994; 91: 8969-8973.
221. Oshima M, Oshima H, Kitagawa K, et al. Loss of Apc heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncated Ape gene. Proc Natl Acad Sci USA 1995; 92: 4482-4486
222. Sharan SK, Morimatsu M, Albrecht L, et al. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca-2. Nature 1997; 386: 804-811.
223. Sirard C, de la Pompa JL, Elia A, et al. The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo. Genes Dev 1998; 12: 107-119.
224. Fazeli A, Dickinson SL, Hermiston ML, et al. Phenotype of mice lacking functional deleted in colorectal cancer (Dec) gene. Nature 1997; 386: 796-804.
225. Reitmar AH, Schmits R, Ewel A, et al. Msh2 deficient mice are viable and susceptible to lymphoid tumors. Nature Genet 1995; 11: 64-70.
226. Reitmar AH, Redston M, Cai JC, et al. Spontaneous intestinal carcinomas and skin neoplasms in Msh-2 deficient mice. Cancer Res 1996; 56: 3842-3849.
227. Baker SM, Bronner CE, Zhang I, et al. Male mice defective in the DNA mismatch repair gene Pms2 exhibit abnormal chromosome synapsis in meiosis. Cell 1995; 82: 309-320.
228. Prolla TA, Baker SM, Harris AC, et al. Tumor susceptibility and spontaneous mutation in mice deficient for M1h1, Pms1 and Pms2 DNA mismatch pair. Nature Genet 1998; 18: 276-279.
229. Edelman W, Yang K, Umar A, et al. Mutation in the mismatch repair gene Msh6 causes cancer susceptibility. Cell 1997; 91: 467-477.
230. Pan H, Yin C, Dyson N, et al. A key role for E2F-1 in p53-dependent apoptosis and cell division within developing tumours. Mol Cell 1998; 2: 283-292.
231. Lifsted T, Le Voyer T, Williams M, et al. Identification of inbred mouse strains harboring genetic modifiers of mammary tumor age of onset and metastatic progression. Int J Cancer 1998; 77: 640-644.
232. Vooijs, M, Van der Valk, M, te Riele, H, Berns A. Flp-mediated tissue-specific inactivation of the retinoblastoma tumor suppressorgene in mouse. Oncogene 1998; 17: 1-12.