Beneath the complexity and idiopathy of every cancer lies a limited number of 'mission critical' events that have propelled the tumour cell and its progeny into uncontrolled expansion and invasion. One of these is deregulated cell proliferation, which, together with the obligate compensatory suppression of apoptosis needed to support it, provides a minimal 'platform' necessary to support further neoplastic progression. Adroit targeting of these critical events should have potent and specific therapeutic consequences.
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Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).
Oller, A. R., Rastogi, P., Morgenthaler, S. & Thilly, W. G. A statistical model to estimate variance in long term-low dose mutation assays: testing of the model in a human lymphoblastoid mutation assay. Mutat. Res. 216, 149–161 (1989).
Evan, G. & Littlewood, T. A matter of life and cell death. Science 281, 1317–1322 (1998).
Pardee, A. B. G1 events and regulation of cell proliferation. Science 246, 603–608 (1989).
Roovers, K. & Assoian, R. K. Integrating the MAP kinase signal into the G1 phase cell cycle machinery. BioEssays 22, 818–826 (2000).
Massague, J., Blain, S. W. & Lo, R. S. TGFβ signaling in growth control, cancer, and heritable disorders. Cell 103, 295–309 (2000).
Sangfelt, O., Erickson, S. & Grander, D. Mechanisms of interferon-induced cell cycle arrest. Front. Biosci. 5, D479–D487 (2000).
Zhu, L. & Skoultchi, A. I. Coordinating cell proliferation and differentiation. Curr. Opin. Genet. Dev. 11, 91–97 (2001).
Bach, S. P., Renehan, A. G. & Potten, C. S. Stem cells: the intestinal stem cell as a paradigm. Carcinogenesis 21, 469–476 (2000).
Booth, C. & Potten, C. S. Gut instincts: thoughts on intestinal epithelial stem cells. J. Clin. Invest. 105, 1493–1499 (2000).
Fuchs, E. & Segre, J. A. Stem cells: a new lease on life. Cell 100, 143–155 (2000).
Raff, M. C. Social controls on cell survival and cell death. Nature 356, 397–400 (1992).
Raff, M. et al. Programmed cell death and the control of cell survival: lessons from the nervous system. Science 262, 695–700 (1993).
DePinho, R. A. The age of cancer. Nature 408, 248–254 (2000).
Hunter, T. Signaling—2000 and beyond. Cell 100, 113–127 (2000).
Harbour, J. W. & Dean, D. C. The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev. 14, 2393–2409 (2000).
Sherr, C. J. Cancer cell cycles. Science 274, 1672–1677 (1996).
Baudino, T. A. & Cleveland, J. L. The Max network gone mad. Mol. Cell. Biol. 21, 691–702 (2001).
Stocker, H. & Hafen, E. Genetic control of cell size. Curr. Opin. Genet. Dev. 10, 529–535 (2000).
Johnston, L. A., Prober, D. A., Edgar, B. A., Eisenman, R. N. & Gallant, P. Drosophila myc regulates cellular growth during development. Cell 98, 779–790 (1999).
Iritani, B. M. & Eisenman, R. N. c-Myc enhances protein synthesis and cell size during B lymphocyte development. Proc. Natl Acad. Sci. USA 96, 13180–13185 (1999).
Elend, M. & Eilers, M. Cell growth: downstream of Myc—to grow or to cycle? Curr. Biol. 9, R936–R938 (1999).
Dang, C. V. et al. Function of the c-Myc oncogenic transcription factor. Exp. Cell Res. 253, 63–77 (1999).
Pelengaris, S., Littlewood, T., Khan, M., Elia, G. & Evan, G. Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion. Mol. Cell 3, 565–577 (1999).
Pelengaris, S., Rudolph, B. & Littlewood, T. Action of Myc in vivo—proliferation and apoptosis. Curr. Opin. Genet. Dev. 10, 100–105 (2000).
Gu, W. et al. Interaction of myogenic factors and the retinoblastoma protein mediates muscle cell commitment and differentiation. Cell 72, 309–324 (1993).
Lasorella, A., Noseda, M., Beyna, M. & Iavarone, A. Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins. Nature 407, 592–598 (2000).
Walczak, H. & Krammer, P. H. The CD95 (APO-1/Fas) and the TRAIL (APO-2L) apoptosis systems. Exp. Cell Res. 256, 58–66 (2000).
Vander Heiden, M. G. et al. Outer mitochondrial membrane permeability can regulate coupled respiration and cell survival. Proc. Natl Acad. Sci. USA 97, 4666–4671 (2000).
Hengartner, M. O. The biochemistry of apoptosis. Nature 407, 770–776 (2000).
Puthalakath, H., Huang, D. C., O'Reilly, L. A., King, S. M. & Strasser, A. The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol. Cell 3, 287–296 (1999).
Yu, H. & Rohan, T. Role of the insulin-like growth factor family in cancer development and progression. J. Natl Cancer Inst. 92, 1472–1489 (2000).
Datta, S. R., Brunet, A. & Greenberg, M. E. Cellular survival: a play in three Akts. Genes Dev. 13, 2905–2927 (1999).
Stambolic, V., Mak, T. W. & Woodgett, J. R. Modulation of cellular apoptotic potential: contributions to oncogenesis. Oncogene 18, 6094–6103 (1999).
Maehama, T. & Dixon, J. E. PTEN: a tumour suppressor that functions as a phospholipid phosphatase. Trends Cell Biol. 9, 125–128 (1999).
Bonneau, D. & Longy, M. Mutations of the human PTEN gene. Hum. Mutat. 16, 109–122 (2000).
Kandel, E. S. & Hay, N. The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp. Cell Res. 253, 210–229 (1999).
Soengas, M. S. et al. Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature 409, 207–211 (2001).
Evan, G. et al. Induction of apoptosis in fibroblasts by c-myc protein. Cell 63, 119–125 (1992).
Askew, D., Ashmun, R., Simmons, B. & Cleveland, J. Constitutive c-myc expression in IL-3-dependent myeloid cell line suppresses cycle arrest and accelerates apoptosis. Oncogene 6, 1915–1922 (1991).
Harrington, E. A., Fanidi, A. & Evan, G. I. Oncogenes and cell death. Curr. Opin. Genet. Dev. 4, 120–129 (1994).
Evan, G. & Littlewood, T. The role of c-myc in cell growth. Curr. Opin. Genet. Dev. 3, 44–49 (1993).
Almasan, A. et al. Deficiency of retinoblastoma protein leads to inappropriate S-phase entry, activation of E2F-responsive genes, and apoptosis. Proc. Natl Acad. Sci. USA 92, 5436–5440 (1995).
Qin, X. Q., Livingston, D. M., Kaelin, W. G. Jr & Adams, P. D. Deregulated transcription factor E2F-1 expression leads to S-phase entry and p53-mediated apoptosis. Proc. Natl Acad. Sci. USA 91, 10918–10922 (1994).
Shan, B. & Lee, W. H. Deregulated expression of E2F-1 induces S-phase entry and leads to apoptosis. Mol. Cell. Biol. 14, 8166–8173 (1994).
Wu, X. & Levine, A. J. p53 and E2F-1 cooperate to mediate apoptosis. Proc. Natl Acad. Sci. USA 91, 3602–3606 (1994).
Dimri, G. P., Itahana, K., Acosta, M. & Campisi, J. Regulation of a senescence checkpoint response by the E2F1 transcription factor and p14(ARF) tumor suppressor. Mol. Cell. Biol. 20, 273–285 (2000).
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, 1519–1523 (1988).
Ferbeyre, G. et al. PML is induced by oncogenic ras and promotes premature senescence. Genes Dev. 14, 2015–2027 (2000).
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, 593–602 (1997).
Fanidi, A., Harrington, E. & Evan, G. Cooperative interaction between c-myc and bcl-2 proto-oncogenes. Nature 359, 554–556 (1992).
Bissonnette, R., Echeverri, F., Mahboubi, A. & Green, D. Apoptotic cell death induced by c-myc is inhibited by bcl-2. Nature 359, 552–554 (1992).
Wagner, A. J., Small, M. B. & Hay, N. Myc-mediated apoptosis is blocked by ectopic expression of bcl-2. Mol. Cell. Biol. 13, 2432–2440 (1993).
Harrington, E. A., Bennett, M. R., Fanidi, A. & Evan, G. I. c-Myc-induced apoptosis in fibroblasts is inhibited by specific cytokines. EMBO J. 13, 3286–3295 (1994).
Strasser, A., Harris, A. W., Bath, M. L. & Cory, S. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature 348, 331–333 (1990).
Phillips, A. C., Ernst, M. K., Bates, S., Rice, N. R. & Vousden, K. H. E2F-1 potentiates cell death by blocking anti-apoptotic signaling pathways. Mol. Cell. 4, 771–781 (1999).
Hueber, A.-O. et al. Requirement for the CD95 receptor-ligand pathway in c-Myc induced apoptosis. Science 278, 1305–1309 (1997).
Klefstrom, J. et al. c-Myc induces cellular susceptibility to the cytotoxic action of TNF-α. EMBO J. 13, 5442–5450 (1994).
Lutz, W., Fulda, S., Jeremias, I., Debatin, K. M. & Schwab, M. MycN and IFNγ cooperate in apoptosis of human neuroblastoma cells. Oncogene 17, 339–346 (1998).
Sherr, C. J. & Weber, J. D. The ARF/p53 pathway. Curr. Opin. Genet. Dev. 10, 94–99 (2000).
Woods, D. B. & Vousden, K. H. Regulation of p53 function. Exp. Cell Res. 264, 56–66 (2001).
Frame, S. et al. Epithelial carcinogenesis in the mouse: correlating the genetics and the biology. Phil. Trans. R. Soc. Lond. B 353, 839–845 (1998).
Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).
Jacobs, J. J., Kieboom, K., Marino, S., DePinho, R. A. & van Lohuizen, M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397, 164–168 (1999).
Maestro, R. et al. twist is a potential ongogene that inhibits apoptosis. Genes Dev. 13, 2207–2217 (1999).
Jacobs, J. J. et al. Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19ARF) and is amplified in a subset of human breast cancers. Nature Genet. 26, 291–299 (2000).
Esteller, M. et al. Hypermethylation-associated inactivation of p14(ARF) is independent of p16(INK4a) methylation and p53 mutational status. Cancer Res. 60, 129–133 (2000).
Robertson, K. D. & Jones, P. A. The human ARF cell cycle regulatory gene promoter is a CpG island which can be silenced by DNA methylation and down-regulated by wild-type p53. Mol. Cell. Biol. 18, 6457–6473 (1998).
Ries, S. et al. Opposing effects of Ras on p53: transcriptional activation of mdm2 and induction of p19ARF. Cell 103, 321–330 (2000).
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, 813–822 (1993).
Greenhalgh, D. A., Wang, X. J., Donehower, L. A. & Roop, D. R. Paradoxical tumor inhibitory effect of p53 loss in transgenic mice expressing epidermal-targeted v-rasHa, v-fos, or human transforming growth factor alpha. Cancer Res. 56, 4413–4423 (1996).
Wang, X. J., Greenhalgh, D. A., Donehower, L. A. & Roop, D. R. Cooperation between Ha-ras and fos or transforming growth factor alpha overcomes a paradoxic tumor-inhibitory effect of p53 loss in transgenic mouse epidermis. Mol. Carcinogenesis 29, 67–75 (2000).
Counter, C. M. et al. Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J. 11, 1921–1929 (1992).
Lengauer, C., Kinzler, K. W. & Vogelstein, B. Genetic instabilities in human cancers. Nature 396, 643–649 (1998).
Rutherford, S. L. & Lindquist, S. Hsp90 as a capacitor for morphological evolution. Nature 396, 336–342 (1998).
Schmitt, C. A. & Lowe, S. W. Apoptosis and therapy. J. Pathol. 187, 127–137 (1999).
Gibbs, J. B. Mechanism-based target identification and drug discovery in cancer research. Science 287, 1969–1973 (2000).
Felsher, D. W. & Bishop, J. M. Reversible tumorigenesis by myc in hematopoietic lineages. Mol. Cell 4, 199–207 (1999).
Chin, L. et al. Essential role for oncogenic Ras in tumour maintenance. Nature 400, 468–472 (1999).
Brandvold, K. A., Neiman, P. & Ruddell, A. Angiogenesis is an early event in the generation of myc-induced lymphomas. Oncogene 19, 2780–2785 (2000).
Breit, S. et al. The N-myc oncogene in human neuroblastoma cells: down-regulation of an angiogenesis inhibitor identified as activin A. Cancer Res. 60, 4596–4601 (2000).
Ngo, C. V. et al. An in vivo function for the transforming Myc protein: elicitation of the angiogenic phenotype. Cell Growth Differ. 11, 201–210 (2000).
Janz, A., Sevignani, C., Kenyon, K., Ngo, C. V. & Thomas-Tikhonenko, A. Activation of the myc oncoprotein leads to increased turnover of thrombospondin-1 mRNA. Nucleic Acids Res. 28, 2268–2275 (2000).
O'Dwyer, M. E. & Druker, B. J. Status of bcr-abl tyrosine kinase inhibitors in chronic myelogenous leukamia. Curr. Opin. Oncol. 12, 594–597 (2000).
Morin, M. J. From oncogene to drug: development of small molecule tyrosine kinase inhibitors as anti-tumor and anti-angiogenic agents. Oncogene 19, 6574–6583 (2000).
Krek, W. VHL takes HIF's breath away. Nature Cell Biol. 2, E1–E3 (2000).
Huang, Y. Q., Li, J. J. & Karpatkin, S. Thrombin inhibits tumor cell growth in association with up-regulation of p21(waf/cip1) and caspases via a p53-independent, STAT-1-dependent pathway. J. Biol. Chem. 275, 6462–6468 (2000).
Komarov, P. G. et al. A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science 285, 1733–1737 (1999).
Chen, Y. N. et al. Selective killing of transformed cells by cyclin/cyclin-dependent kinase 2 antagonists. Proc. Natl Acad. Sci. USA 96, 4325–4329 (1999).
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Evan, G., Vousden, K. Proliferation, cell cycle and apoptosis in cancer. Nature 411, 342–348 (2001). https://doi.org/10.1038/35077213
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