New roles for the RB tumor suppressor protein

Current Opinion in Genetics and Development

Volumn 14, Issue 1, 2004, Pages 55-64

  Liu, Huiping ^a   Dibling, Benjamin ^a   Spike, Benjamin ^a   Dirlam, Alexandra ^a   Macleod, Kay ^a  

^a UNIVERSITY OF CHICAGO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CAMPTOTHECIN; CISPLATIN; CYCLOPHOSPHAMIDE; ETOPOSIDE; METHOTREXATE; MITOMYCIN; TUMOR SUPPRESSOR PROTEIN;

CANCER CHEMOTHERAPY; CARCINOGENESIS; CELL AGING; DNA DAMAGE; EMBRYO DEVELOPMENT; EMBRYONAL TISSUE; GENE FUNCTION; GENE SILENCING; GENE TARGETING; HOMEOSTASIS; HUMAN; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; REGULATORY MECHANISM; RETINOBLASTOMA; REVIEW; SENESCENCE; SURVIVAL; TISSUE DIFFERENTIATION; TUMOR SUPPRESSOR GENE;

EID: 0842281494     PISSN: 0959437X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.gde.2003.11.005     Document Type: Review

References (102)

1. Weinberg R.A. The retinoblastoma protein and cell cycle control. Cell. 81:1995;323-330.
2. Sherr C.J., McCormick F. The RB and p53 pathways in cancer. Cancer Cell. 2:2002;103-112.
3. Lipinski M.M., Jacks T. The retinoblastoma gene family in differentiation and development. Oncogene. 18:1999;7873-7882.
4. Hahn W.C., Weinberg R.A. Modelling the molecular circuitry of cancer. Nat Rev Cancer. 2:2002;331-341.
5. Hickman E.S., Moroni M.C., Helin K. The role of p53 and pRB in apoptosis and cancer. Curr Opin Genet Dev. 12:2002;60-66.
6. Chau B.N., Wang J.Y. Coordinated regulation of life and death by RB. Nat Rev Cancer. 3:2003;130-138.
7. Stevaux O., Dyson N.J. A revised picture of the E2F transcriptional network and RB function. Curr Opin Cell Biol. 14:2002;684-691.
8. Moroni M.C., Hickman E.S., Denchi E.L., Caprara G., Colli E., Cecconi F., Muller H., Helin K. Apaf-1 is a transcriptional target for E2F and p53. Nat Cell Biol. 3:2001;552-558.
9. Nahle Z., Polakoff J., Davuluri R.V., McCurrach M.E., Jacobson M.D., Narita M., Zhang M.Q., Lazebnik Y., Bar-Sagi D., Lowe S.W. Direct coupling of the cell cycle and cell death machinery by E2F. Nat Cell Biol. 4:2002;859-864 The authors show that inactivation of pRb by over-expression of the E1A oncoprotein induces procaspase expression in a p53- and Arf-independent manner. The authors show that procaspases -3, -7, -8, and -9 are direct transcriptional targets of E2f-1.
10. Sherr M.J., Roberts J.M. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13:1999;1501-1512.
11. Schmitt C.A., Fridman J.S., Yang M., Lee S., Baranov E., Hoffman R.M., Lowe S.W. A senescence program controlled by p53 and p16/Ink4a contributes to the outcome of cancer therapy. Cell. 109:2002;335-346 Using the Eμ-Myc lymphoma model, the authors show that p16/Ink4a-induced senescence promotes improved survival of mice following chemotherapy treatment and suggest that senescence, like apoptosis, is a cellular mechanism utilized by cells to modulate cancer therapy responses.
12. Lowe S.W., Sherr C.J. Tumor suppression by Ink4a-Arf: progress and puzzles. Curr Opin Genet Dev. 13:2003;77-83.
13. Sage J., Miller A.L., Perez-Mancera P.A., Wysocki J.M., Jacks T. Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature. 424:2003;223-228 Germline-targeted Rb null MEFs adapt to cell-culture conditions by up-regulating p107 thus explaining why inactivation of all three pocket proteins is required in these cells to circumvent growth arrest during quiescence and senescence. In contrast, conditionally targeted MEFs only need to inactivate Rb (by Cre-lox recombination) in order to re-enter the cell cycle from either a quiescent or senescent state.
14. Sage J., Mulligan G.J., Attardi L.D., Miller A., Chen S.Q., Williams B., Theodorou E., Jacks T. Targeted disruption of the three Rb-related genes leads to loss of G1 control and immortalisation. Genes Dev. 14:2000;3037-3050.
15. Dannenberg J.H., van Rossum A., Schuijff L., te Riele H. Ablation of the retinoblastoma gene family deregulates G1 control causing immortalisation and increased cell turnover under growth restricting conditions. Genes Dev. 14:2000;3051-3064.
16. Parrinello S., Samper E., Krtolica A., Goldstein J., Melov S., Campisi J. Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat Cell Biol. 5:2003;741-747.
17. Herrera R.E., Sah V.P., Williams B.O., Makela T.P., Weinberg R.A., Jacks T. Altered cell cycle kinetics, gene expression and G1 restriction point regulation in Rb-deficient fibroblasts. Mol Cell Biol. 16:1996;2402-2407.
18. Hurford R.K., Cobrinik D., Lee M.H., Dyson N. pRB and p107/p130 are required for the regulated expression of different sets of E2F responsive genes. Genes Dev. 11:1997;1447-1463.
19. Takahashi Y., Rayman J.B., Dynlacht B.D. Analysis of promoter binding by the E2F and pRB families in vivo: distinct E2F proteins mediate activation and repression. Genes Dev. 14:2000;804-816.
20. Cam H., Dynlacht B.D. Emerging roles for E2F: beyond the G1/S transition and DNA replication. Cancer Cell. 3:2003;311-316.
21. Narita M., Nunez S., Heard E., Narita M., Lin A.W., Hearn S.A., Spector D.L., Hannon G.J., Lowe S.W. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell. 113: 2003;703-716 The authors show that pRB specifically associates with E2F sites in the promoters of cell cycle genes in senescent cells. Using chromatin immunoprecipitation, pRB was found in 'senescence-associated heterochromatic foci' (or 'SAHF') on the promoters of E2F target genes such as cyclin A and PCNA that had been stably repressed or silenced by histone methylation on lysine 9 of histone H3 providing a docking site for the pRB-interacting protein, HP1.
22. Zhang H.S., Gavin M., Dahiya A., Postigo A.A., Ma D., Luo R.X., Harbour J.W., Dean D.C. Exit from G1 and S phase of the cell cycle is regulated by repressor complexes containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF. Cell. 101:2000;79-89.
23. Vandel L., Nicolas E., Vaute O., Ferreira R., Ait-si-ali S., Trouche D. Transcriptional repression by the retinoblastoma protein through recruitment of a histone methyltransferase. Mol Cell Biol. 21:2001;6484-6494.
24. Nielsen S.J., Schneider R., Bauer U.M., Bannister A.J., Morrison A., O'Carroll D., Firestein R., Cleary M., Jenuwein T., Herrera R., Kouzarides T. Rb targets histone methylation and HP1 to promoters. Nature. 412:2001;561-565.
25. Jacks T., Fazeli A., Schmidt E., Bronson R., Goodell M., Weinberg R. Effects of an Rb mutation in the mouse. Nature. 359:1992;295-300.
26. Clarke A.R., Maandag E.R., van Roon M., van der Lugt N.M.T., van der Valk M., Hooper M.L., Berns A., te Riele H. Requirement for a functional Rb-1 gene in murine development. Nature. 359:1992;328-330.
27. Lee E.Y.-H.P., Chang C.-Y., Hu N., Wang Y.-C.J., Lai C.-C., Herrup K., Lee W.-H. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature. 359:1992;288-295.
28. 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. 15:1996;6178-6188.
29. Morgenbesser S.D., Williams B.O., Jacks T., DePinho R.A. p53-dependent apoptosis produced by Rb-deficiency in the developing mouse lens. Nature. 371:1994;72-74.
30. Zacksenhaus E., Jiang Z., Chung D., Marth J.D., Philips R.A., Gallie B.L. pRb controls proliferation, differentiation, and death of skeletal muscle cells and other lineages during embryogenesis. Genes Dev. 10:1996;3051-3064.
31. Williams B.O., Schmitt E.M., Remington L., Bronson R.T., Albert D.M., Weinberg R.A., Jacks T. Extensive contribution of Rb-deficient cells to adult chimeric mice with limited histopathological consequences. EMBO J. 13:1994;4251-4259.
32. Robanus-Maandag E.C., van der Valk M., Vlaar M., Feltkamp C., O'Brien J., van Roon M., van der Lugt N., Berns A., te Riele H. Developmental rescue of an embryonic-lethal mutation in the retinoblastoma gene in chimeric mice. EMBO J. 13:1994;4260-4268.
33. Lipinski M., Macleod K.F., Crowley D., Mullaney T., Jacks T. Cell-autonomous and non-cell autonomous developmental functions of the retinoblastoma tumor suppressor gene in vivo. EMBO J. 20:2001;3402-3413.
34. Raff M.C., Barres B.A., Burne J.F., Coles H.S., Ishizaki Y., Jacobson M.D. Programmed cell death and the control of cell survival: lessons from the nervous system. Science. 262:1993;695-700.
35. Ferguson K.L., Vanderluit J.L., Hebert J.M., McIntosh W.C., Tibbo E., MacLaurin J.G., Park D.S., Wallace V.A., Vooijs M., McConnell S.K., Slack R.S. Telencephalon-specific Rb knockouts reveal enhanced neurogenesis, survival and abnormal cortical development. EMBO J. 21:2002;3337-3346 The authors generated mice in which Rb was conditionally inactivated in the telencephalon by crossing Rb-floxed mice to Foxg1 Cre transgenic mice. Rb null neurons continued to show the proliferation defects (ectopic S phase entry) observed in Rb homozygous mutants but did not show the apoptosis that is widespread in the CNS of the Rb homozygous mutants.
36. Macpherson D., Sage J., Crowley D., Trumpp A., Bronson R.T., Jacks T. Conditional mutation of Rb causes cell cycle defects without apoptosis in the central nervous system. Mol Cell Biol. 23:2003;1044-1053 In this study, nestin-Cre transgenic mice were used to conditionally target Rb loss to the nervous system. Inactivation of Rb in the nervous system resulted in ectopic S phase entry but no apoptosis, resulting in an enlarged brain in these mice that survived longer in development than the homozygous mutant embryo. Demonstrating induced expression of hypoxia-inducible genes, the authors suggest that the apoptosis observed in the Rb null CNS was a result of the erythroid defects in the embryo.
37. Wu L., de Bruin A., Saavedra H.I., Starivic M., Trimboli A., Yang Y., Opavska J., Wilson P., Thompson J.C., Ostrowski M.C.et al. Extra-embryonic function of Rb is essential for embryonic development and viability. Nature. 421:2003;942-947 The authors demonstrate a critical role for pRb in the differentiation of trophoblast stem cells and the consequent defects in the labyrinth layer of the placenta, that result in reduced oxygen/nutrient exchange between the maternal and fetal blood supplies. The authors suggest this may explain the non-cell-autonomous defects in the Rb null embryo and pursue this idea by conditionally targeting Rb in the embryo while leaving it intact in extra-embryonic tissues. This is achieved by crossing Rb-floxed mice to Meox2-Cre transgenic mice and is further supported by the results of tetraploid aggregation experiments. The authors show rescue of cell death in the nervous system of the Rb null embryo and survival of the embryo to birth. Defects in lens and erythroid maturation are still apparent in these mice.
38. de Bruin A., Wu S., Wilson P., Yang Y., Rosol T.J., Weinstein M., Robinson M.L., Leone G. Rb function in extraembryonic tissue lineages suppresses apoptosis in the CNS of Rb-deficient mice. Proc Natl Acad Sci USA. 100:2003;6546-6551.
39. Spike BT, Dibling B, Green M, Williams BO, Jacks T, Macleod KF: Cell intrinsic defects in Rb null hematopoiesis. Genes Dev 2003, in press.
40. Zhang P., Wong C., DePinho R.A., Harper J.W., Elledge S.J. Cooperation between the cdk inhibitors p27KIP1 and p57KIP2 in the control of tissue growth and development. Genes Dev. 12:1998;3162-3167.
41. MacAuley A., Cross J.C., Werb Z. Reprogramming the cell cycle for endoreduplication in rodent trophoblast cells. Mol Biol Cell. 9:1998;795-807.
42. Hattori N., Vavies T.C., Anson-Cartwright L., Cross J.C. Periodic expression of the cyclin-dependent kinase inhibitor p57/Kip2 in trophoblast giant cells defines a G2-like gap phase of the endocycle. Mol Biol Cell. 11:2000;1037-1045.
43. Ravid K., Lu J., Zimmet J.M., Jones M.R. Roads to polyploidy: the megakaryocyte example. J Cell Physiol. 190:2002;7-20.
44. Geng Y., Yu Q., Sicinska E., Das M., Schneider J.E., Bhattacharya S., Rideout W.M., Bronson R.T., Gardner H., Sicinski P. Cyclin E ablation in the mouse. Cell. 114:2003;431-443 Germ-line targeting of cyclins E1 and E2 demonstrate that E-type cyclins are required for trophoblast differentiation and placental development. Tetraploid aggregation is used to show that E-type cyclins are dispensable for embryonic development despite their requirement for extra-embryonic tissues. Cyclin E deficient mice develop cardiac problems around birth. Cyclin E is also required for endoreduplication in megakaryocytes.
45. Li F.X., Zhu J.W., Hogan C.J., DeGregori J. Defective gene expression, S phase progression and maturation during hematopoiesis in E2F1/E2F2 mutant mice. Mol Cell Biol. 23:2003;3607-3622.
46. Ciemerych M.A., Kenney A.M., Sicinska E., Kalaszczynska I., Bronson R.T., Rowitch D.H., Gardner H., Sicinski P. Development of mice expressing a single D-type cyclin. Genes Dev. 16:2002;3277-3289 Mice expressing only one of the three mammalian D-type cyclins, D1, D2 or D3, were generated by gene targeting and interbreeding. Single D cyclin embryos survive to late stages of development and up-regulate the remaining cyclin in tissues where the other two would have been expressed suggesting that the D-type cyclins are functionally interchangeable and differ mainly in their pattern of expression. Cyclin-D1-only mice develop megaloblastic anemia suggesting that one of the other two cyclins, most likely D3 given its expression pattern, has important functions in blood development.
47. Tsai K.Y., Hu Y., Macleod K.F., Crowley D., Yamasaki L., Jacks T. Mutation of E2f-1 suppresses apoptosis and inappropriate S-phase entry and extends survival of Rb-deficient mouse embryos. Mol Cell. 2:1998;283-292.
48. Ziebold U., Reza T., Caron A., Lees J.A. E2F3 contributes both to the inappropriate proliferation and to the apoptosis arising in Rb mutant embryos. Genes Dev. 15:2001;386-391.
49. An W.G., Kanekal M., Simon M.C., Maltepe E., Blagosklonny M.V., Neckers L.M. Stabilisation of wild-type p53 by hypoxia-inducible factor1α Nature. 392:1998;405-408.
50. Graeber T.G., Osmanian C., Jacks T., Housman D.E., Koch C.J., Lowe S.W., Giaccia A.J. Hypoxia mediated selection of cells with diminished apoptotic potential in solid tumors. Nature. 379:1996;88-91.
51. Lasorella A., Noseda M., Beyna M., Iavarone A. Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins. Nature. 407:2000;592-598.
52. Janatpour M.J., McMaster M.T., Genbacev O., Zhou Y., Dong J.Y., Cross J.C., Israel M.A., Fisher S.J. Id-2 regulates critical aspects of human cytotrophoblast differentiation, invasion and migration. Development. 127:2000;549-558.
53. Marino S., Hoogervoorst D., Brandner S., Berns A. Rb and p107 are required for normal cerebellar development and granule cell survival but not for Purkinje cell persistence. Development. 130:2003;3359-3368.
54. Ruiz S, Santos M, Segrelles C, Leis H, Jorcano JL, Berns A, Paramio JM, Vooijs M: Unique and overlapping functions of Rb and p107 in the control of epidermal proliferation and differentiation. Personal communication.
55. Classon M., Kennedy B., Mulloy R., Harlow E. Opposing roles of pRB and p107 in adipocyte differentiation. Proc Natl Acad Sci USA. 97:2000;10826-10831.
56. Landsberg R.L., Sero J.E., Danielian P.S., Yuan T.L., Lee E.Y., Lees J.A. The role of E2F4 in adipogenesis is independent of its cell cycle regulatory activity. Proc Natl Acad Sci USA. 100:2003;2456-2461 By examining the ability of MEFs, mutant for different E2F and pocket proteins, to differentiate into adipocytes under the influence of hormones, the authors examined the roles of E2F4, p107 and p130 in promoting terminal adipocyte differentiation. E2f4 deficient MEFs undergo adipogenesis spontaneously without hormones in a manner independent of p107 or p130 that appear to inhibit differentiation. The activity of E2f4 in this differentiation assay is separable from its ability to promote growth arrest.
57. Otterson G.A., Chen W., Coxon A.B., Khleif S.N., Kaye F.J. Incomplete penetrance of familial retinoblastoma linked to germ-line mutations that result from partial loss of RB function. Proc Natl Acad Sci USA. 94:1997;12036-12040.
58. Sellers W.R., Novitch B.G., Miyake S., Heith A., Otterson G.A., Kaye F.J., Lassar A.B., Kaelin W.G. Stable binding to E2F is not required for the retinoblastoma protein to activate transcription, promote differentiation and suppress tumor cell growth. Genes Dev. 12:1998;95-106.
59. Harbour J.W. Molecular basis of low-penetrance retinoblastoma. Arch Ophthalmol. 119:2001;1699-1704.
60. Thomas D.M., Carty S.A., Piscopo D.M., Lee J., Wang W., Forrester W.C., Hinds P.W. Retinoblastoma protein acts as a transcriptional coactivator required for osteogenic differentiation. Mol Cell. 8:2001;303-316.
61. Dimova D.K., Stevaux O., Frolov M.V., Dyson N.J. Cell cycle-dependent and cell cycle-independent control of transcription by the Drosophila E2F/RB pathway. Genes Dev. 17:2003;2308-2320 By knocking down individual components of the Drosophila RB/E2F families using RNAi, the authors identify distinct programs of gene expression regulated by specific groups of RB/E2F. dE2F1/RBF1 regulates the classic group of E2F target genes required for cell-cycle progression. The striking observation is that dE2F2/RBF1 and dE2F2/RBF2 repress a distinct program of differentiation factors in proliferating cells and presumably allow their derepression in differentiating tissues. Surprisingly, the regulation of these genes is also gender specific.
62. Muller H., Bracken A.P., Vernell R., Moroni M.C., Christians F., Grassilli E., Prosperini E., Vigo E., Oliner J.D., Helin K. E2Fs regulate the expression of genes involved in differentiation, development, proliferation and apoptosis. Genes Dev. 15:2001;267-285.
63. Slomiany B.A., D'Arigo K.L., Kelly M.M., Kurtz D.T. C/EBPα inhibits cell growth via direct repression of E2F-DP mediated transcription. Mol Cell Biol. 20:2000;5986-5997.
64. Porse B.T., Pedersen T.A., Xu X., Lindberg B., Wewer U.M., Frils-Hansen L., Nerlov C. E2F repression by C/EBPα is required for adipogenesis and granulopoiesis in vivo. Cell. 107:2001;247-258.
65. Friedman A.D. Transcriptional regulation of granulocyte and monocyte differentiation. Oncogene. 21:2002;3377-3390.
66. Fajas L., Landsberg R.L., Huss-Garcia Y., Sardet C., Lees J.A., Auwerx J. E2Fs regulate adipocyte differentiation. Dev Cell. 3:2002;39-49.
67. Klappacher G.W., Lunyak V.V., Sykes D.B., Sawka-Verhelle D., Sage J., Brard G., Ngo S.D., Gangadharan D., Jacks T., Kamps M.P.et al. An induced Ets repressor complex regulates growth arrest during macrophage differentiation. Cell. 109:2002;169-180 The authors identify a repressor of Ets transactivation in differentiating macrophages, termed METS, which blocks Ras-induced proliferation and is dependent on the function of members of the RB/E2F family for activity.
68. Spike BT, Macleod KF: Loss of pRb and p53 cooperates in the genesis of acute myeloid leukemia. J Exp Hematol 2003, in press.
69. Meuwissen R., Linn S.C., Linnoila R.I., Zevenhoven J., Mooi W.J., Berns A. Induction of small cell lung cancer by somatic inactivation of both Trp53 and Rb1 in a conditional mouse model. Cancer Cell. 4:2003;181-189 The authors examine the effects of combined Rb and p53 loss on tumorigenesis in the lung and demonstrate that although the entire lung epithelium is targeted for Cre-mediated recombination, neuroendocrine tumors are the tumor type to emerge suggesting a unique function for these genes in the homeostasis of lung neuroendocrine cells.
70. Shackney S.E., Shankey T.V. Common patterns of genetic evolution in human solid tumors. Cytometry. 29:1997;1-27.
71. Eischen C.M., Weber J.D., Roussel M.F., Sherr C.J., Cleveland J.L. Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev. 13:1999;2658-2669.
72. Schmitt C.A., McCurrach M.E., de Stanchina E., Wallace-Brodeur R.R., Lowe S.W. INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53. Genes Dev. 13:1999;2670-2677.
73. Evan G., Littlewood T. A matter of life and death. Science. 281:1998;1317-1322.
74. Symonds H., Krall L., Remington L., Saenz-Robles M., Lowe S., Jacks T., Van Dyke T. p53-dependent apoptosis suppresses tumor growth and progression in vivo. Cell. 78:1994;703-711.
75. Williams B.O., Remington L., Bronson R.T., Mukai S., Albert D.M., Dryja T., Jacks T. Cooperative tumorigenic effects of germline mutations in Rb and p53. Nat Genet. 7:1994;480-484.
76. Green D.R., Evan G.I. A matter of life and death. Cancer Cell. 1:2002;19-30.
77. Almasan A., Yin Y., Kelly R., Lee Y.-H.P., Bradley A., Li W., Bertino J.R., Wahl G.M. Deficiency of retinoblastoma protein leads to inappropriate S-phase entry, activation of E2F-responsive genes and apoptosis. Proc Natl Acad Sci USA. 92:1995;5436-5440.
78. Harrington E.A., Bruce J.L., Harlow E., Dyson N. pRB plays an essential role in cell cycle arrest induced by DNA damage. Proc Natl Acad Sci USA. 95:1998;11945-11950.
79. Knudsen K.E., Booth D., Naderi S., Sever-Chroneos Z., Fribourg A.F., Hunton I.C., Feramisco J.R., Wang J.Y.J., Knudsen E.S. RB-dependent S-phase response to DNA damage. Mol Cell Biol. 20:2000;7751-7763.
80. DeGregori J., Leone G., Miron A., Jakoi L., Nevins J.R. Distinct roles for E2F proteins in cell growth control and apoptosis. Proc Natl Acad Sci USA. 94:1997;7245-7250.
81. Leone G., Sears R., Huang E., Rempel R., Nuckolls F., Park C., Giangrande P., Wu L., Saavedra H.I., Field S.J., Thompson M.A., Yang H., Fujiwara Y., Greenberg M.E., Orkin S.H., Smith C., Nevins J.R. Myc requires distinct E2F activities to induce S phase and apoptosis. Mol. Cell. 8:2001;105-113.
82. ••,71, 72] were in this study crossed with E2f1-deficient mice to show that loss of even one allele of E2f1 retarded tumor cell proliferation but had little effect on the incidence of apoptosis in the B-cell lymphomas that did develop. Consistent with these observations, the frequency of p53 and Arf mutations in lymphomas was unaffected by E2f1 loss. The ability of Myc to promote proliferation in an E2f1-dependent manner was in turn dependent on increased turnover of the p27 Kip1 Cdk inhibitor.
83. Dick F.A., Dyson N. pRB contains an E2F1-specific binding domain that allows E2F1-induced apoptosis to be regulated separately from other E2F activities. Mol Cell. 12:2003;639-649 The authors generated a mutant form of pRB, termed RBΔE2F-G, by substitution of 11 amino acids in the pocket domain that has dramatically reduced affinity for E2Fs and is also defective for repression of E2Fs in transactivation assays. However, the RBΔE2F-G mutant retains E2F1-binding ability that is mediated by the C domain of pRB and N-terminal sequences of E2F1 that includes its DNA-binding domain. This 'S' type interaction, as the authors have termed it, results in loss of E2F1 DNA binding activity and inhibition of E2F1-induced apoptosis. The interaction is lost following treatment of cells with DNA damaging agents.
84. Lin W., Lin F., Nevins J.R. Selective induction of E2F1 in response to DNA damage, mediated by ATM-dependent phosphorylation. Genes Dev. 15:2001;1833-1844.
85. Bates S., Phillips A.C., Clark P.A., Stott F., Peters G., Ludwig R.L., Vousden K.H. p14ARF links the tumor suppressors RB and p53. Nature. 395:1998;124-125.
86. Ryo A., Liou Y., Wulf G., Nakamura M., Lee S.W., Lu K.P. PIN1 is an E2F target gene essential for Neu/Ras induced transformation of mammary epithelial cells. Mol Cell Biol. 22:2002;5281-5295 The Pin1 prolyl isomerase induces conformational changes in proteins following Ser-/Thr-Pro phosphorylation. Key targets of Pin1 include p53, and cyclin D1 and inhibition of Pin1 suppresses Neu- and Ras- transformation. The authors show here that E2F regulates transcription of Pin1 through several functional E2F sites in the proximal region of the Pin1 promoter.
87. Pomerantz J., Schreiber-Agus N., Liegois N.J., Silverman A., Alland L., Chin L., Potes J., Chen K., Orlow I., Lee H.et al. The Ink4a tumor suppressor gene product p19ARF interacts with mdm2 and neutralises mdm2's inhibition of p53. Cell. 92:1998;713-723.
88. Zheng H., You H., Zhou X., Murray S.A., Uchida T., Wulf G., Gu L., Tang X., Lu K.P., Xiao Z.J. The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response. Nature. 419:2002;849-853 The Pin1 prolyl isomerase regulates p53 activity in response to DNA damage by inducing activating conformational changes of serine phosphorylated p53. Pin1-null MEFs show reduced p53 induction in response to DNA damage.
89. ••] show similar data demonstrating that the interaction between p53 and Pin1 is dependent on serine/threonine phosphorylation of p53 on residues 33, 81 and 315 and that this interaction is required for activation of p53 following DNA damage. Pin1 null cells were defective for p53 activation.
90. Zindy F., Eischen C.M., Randle D.H., Kamijo T., Cleveland J.L., Sherr C.J., Roussel M.F. Myc signalling via the ARF tumor suppressor regulates p53-dependent apoptosis. Genes Dev. 12:1998;2424-2433.
91. 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.
92. de Stanchina E., McCurrach M.E., Zindy F., Shieh S.Y., Ferbeyre G., Samuelson A.V., Prives C., Roussel M.F., Sherr C.J., Lowe S.W. E1A signalling to p53 involves the 19ARF tumor suppressor. Genes Dev. 12:1998;2434-2442.
93. Giaccia A.J., Kastan M.B. The complexity of p53 modulation: emerging patterns from divergent signals. Genes Dev. 12:1998;2973-2983.
94. L deamidation are not yet clear.
95. Alexander K., Hinds P.W. Requirement for p27KIP1 in retinoblastoma protein-mediated senescence. Mol Cell Biol. 21:2001;3616-3631.
96. Amundson S.A., Myers T.G., Scudiero D., Kitada S., Reed J.C., Fornace A.J. Jnr. An informatics approach identifying markers of chemosensitivity in human cancer cell lines. Cancer Res. 60:2000;6101-6110.
97. L.
98. Lowe S.M., Ruley H.E., Jacks T., Housman D.E. p53-dependent apoptosis modulates the cytoxicity of anticancer agents. Cell. 74:1993;957-967.
99. Lowe S.W., Bodis S., McClatchey A., Remington L., Ruley H.E., Fisher D.E., Housman D.E., Jacks T. p53 status and the efficacy of cancer therapy in vivo. Science. 266:1994;807-810.
100. Brown J.M., Wouters B.G. Apoptosis, p53 and tumor cell sensitivity to anticancer agents. Cancer Res. 59:1999;1391-1399.
101. Hawkins D.S., Demers G.W., Galloway D.A. Inactivation of p53 enhances sensitivity to multiple chemotherapeutic agents. Cancer Res. 56:1996;892-898.
102. Fan S., Smith M.L., Rivet D.J., Duba D., Zhan Q., Kohn K.W., Fornace A.J. Jnr., O'Connor P.M. Disruption of p53 function sensitizes breast cancer MCF-7 cells to cis-platin and pentoxyfylline. Cancer Res. 55:1995;1649-1654.