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The INK4A/Arf Network — Cell Cycle Checkpoint or Emergency Brake?

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Genome Instability in Cancer Development

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References

  • Agami, R., and R. Bernards. 2000. Distinct initiation and maintenance mechanisms cooperate to induce G1 cell cycle arrest in response to DNA damage. Cell. 102:55–66.

    Article  CAS  PubMed  Google Scholar 

  • Alcorta, D.A., Y. Xiong, D. Phelps, G. Hannon, D. Beach, and J.C. Barrett. 1996. Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence. Proc. Natl. Acad. Sci. USA. 93:13742–13747.

    Article  CAS  PubMed  Google Scholar 

  • Aslanian, A., P.J. Iaquinta, R. Verona, and J.A. Lees. 2004. Repression of the Arf tumor suppressor by E2F3 is required for normal cel cycle kinetics. Genes & Dev. 18:1413–1422.

    CAS  Google Scholar 

  • Bates, S., A.C. Phillips, P.A. Clark, F. Stott, G. Peters, R.L. Ludwig, and K.H. Vousden. 1998. p14ARF links the tumour suppressors RB and p53. Nature. 395:124–125.

    CAS  PubMed  Google Scholar 

  • Benanti, J.A., and D.A. Galloway. 2004. Normal human fibroblasts are resistant to RAS-induced senescence. Mol. Cell. Biol. 24:2842–2852.

    Article  CAS  PubMed  Google Scholar 

  • Bertwistle, D., M. Sugimoto, and C.J. Sherr. 2004. Physical and functional interactions of the Arf tumor suppressor protein with nucleophosmin/B23. Mol. Cell. Biol. 24:985–996.

    Article  CAS  PubMed  Google Scholar 

  • Blattner, C., A. Sparks, and D. Lane. 1999. Transcription factor E2F-1 is upregulated in response to DNA damage in a manner analogous to that of p53. Mol. Cell. Biol. 19:3704–3713.

    CAS  PubMed  Google Scholar 

  • Bodnar, A.G., M. Ouellette, M. Frolkis, S.E. Holt, C.-P. Chiu, G.B. Morin, C.B. Harley, J.W. Shay, S. Lichsteiner, and W.E. Wright. 1998. Extension of life-span by introduction of telomerase into normal human cells. Science. 279:349–352.

    Article  CAS  PubMed  Google Scholar 

  • Bothner, B., W.S. Lewis, E.L. DiGiammarino, J.D. Weber, S.J. Bothner, and R.W. Kriwacki. 2001. Defining the molecular basis of Arf and Hdm2 interactions. J. Mol. Biol. 314:263–277.

    Article  CAS  PubMed  Google Scholar 

  • Brenner, A.J., M.R. Stampfer, and C.M. Aldaz. 1998. Increased p16 expression with first senescence arrest in human mammary epithelial cells and extended growth capacity with p16 inactivation. Oncogene. 17:199–205.

    Article  CAS  PubMed  Google Scholar 

  • Brookes, S., J. Rowe, A. Gutierrez del Arroyo, J. Bond, and G. Peters. 2004. Contribution of p16INK4a to replicative senescence of human fibroblasts. Exp. Cell Res. 298:549–559.

    Article  CAS  PubMed  Google Scholar 

  • Brookes, S., J. Rowe, M. Ruas, S. Llanos, P.A. Clark, M. Lomax, M.C. James, R. Vatcheva, S. Bates, K.H. Vousden, D. Parry, N. Gruis, N. Smit, W. Bergman, and G. Peters. 2002. INK4a-deficient human diploid fibroblasts are resistant to RAS-induced senescence. EMBO J. 21:2936–2945.

    Article  CAS  PubMed  Google Scholar 

  • Bulavin, D.V., O.N. Demidov, S. Saito, P. Kauraniemi, C. Phillips, S.A. Amundson, C. Ambrosino, G. Sauter, A.R. Nebreda, C.W. Anderson, A. Kallioniemi, A.J. Fornace Jr., and E. Appella. 2002. Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity. Nat. Genet. 31:210–215.

    Article  CAS  PubMed  Google Scholar 

  • Bulavin, D.V., S. Saito, M.C. Hollander, K. Sakaguchi, C.W. Anderson, E. Appella, and A.J. Fornace Jr. 1999. Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation. EMBO J. 18:6845–6854.

    Article  CAS  PubMed  Google Scholar 

  • Buschmann, T., V. Adler, E. Matusevich, S.Y. Fuchs, and Z. Ronai. 2000. p53 phosphorylation and association wih murine double minute 2, c-Jun NH2-terminal kinase, p14ARF, and p300/CBP during the cell cycle and after exposure to ultraviolet irradiation. Cancer Res. 60:896–900.

    CAS  PubMed  Google Scholar 

  • Campisi, J. 1997. The biology of replicative senescence. Eur. J. Cancer. 33:703–709.

    Article  CAS  PubMed  Google Scholar 

  • Chen, Q., A. Fischer, J.D. Reagan, L.J. Yan, and B.N. Ames. 1995. Oxidative DNA damage and senescence of human diploid fibroblast cells. Proc. Natl. Acad. Sci. USA. 92:4337–4341.

    CAS  PubMed  Google Scholar 

  • Clark, P.A., S. Llanos, and G. Peters. 2002. Multiple interacting domains contribute to p14ARF mediated inhibition of MDM2. Oncogene. 21:4498–4507.

    CAS  PubMed  Google Scholar 

  • d’Adda di Fagagna, F., P.M. Reaper, L. Clay-Farrace, H. Fiegler, P. Carr, T. von Zglinicki, G. Saretzki, N.P. Carter, and S.P. Jackson. 2003. A DNA damage checkpoint response in telomere-initiated senescence. Nature. 426:194–198.

    Google Scholar 

  • Datta, A., A. Nag, W. Pan, N. Hay, A.L. Gartel, O. Colamonici, Y. Mori, and P. Raychaudhuri. 2004. Myc-ARF (alternative reading frame) interaction inhibits the functions of Myc. J. Biol. Chem. 279:36698–36707.

    CAS  PubMed  Google Scholar 

  • Datta, B., A. Nag, and P. Raychaudhuri. 2002. Differential regulation of E2F1, DP1, and the E2F1/DP1 complex by ARF. Mol. Cell. Biol. 22:8398–8408.

    Article  CAS  PubMed  Google Scholar 

  • De Stanchina, E., M.E. McCurrach, F. Zindy, S.-Y. Shieh, G. Ferbeyre, A.V. Samuelson, C. Prives, M.F. Roussel, C.J. Sherr, and S.W. Lowe. 1998. E1A signaling to p53 involves the p19ARF tumor suppressor. Genes Dev. 12:2434–2442.

    PubMed  Google Scholar 

  • DeGregori, J., G. Leone, A. Miron, L. Jakoi, and J.R. Nevins. 1997. Distinct roles for E2F proteins in cell growth control. Proc. Natl. Acad. Sci. USA. 94:7245–7250.

    Article  CAS  PubMed  Google Scholar 

  • Deng, Q., R. Liao, B.-L. Wu, and P. Sun. 2004. High intensity ras signaling induces premature senescence by activating p38 pathway in primary human fibroblasts. J. Biol. Chem. 279:1050–1059.

    CAS  PubMed  Google Scholar 

  • Dickson, M.A., W.C. Hahn, Y. Ino, V. Ronfard, J.Y. Wu, R.A. Weinberg, D.N. Louis, F.P. Li, and J.G. Rheinwald. 2000. Human keratinocytes that express hTERT and also bypass a p16INK4a-enforced mechanism that limits life span become immortal yet retain normal growth and differentiation characteristics. Mol. Cell. Biol. 20:1436–1447.

    Article  CAS  PubMed  Google Scholar 

  • Dimri, G.P., K. Itahana, M. Acosta, and J. Campisi. 2000. Regulation of a senescence checkpoint response by the E2F1 transcription factor and p14ARF tumor suppressor. Mol. Cell. Biol. 20:273–285.

    Article  CAS  PubMed  Google Scholar 

  • Drayton, S., and G. Peters. 2002. Immortalisation and transformation revisited. Curr. Opin. Genet. Dev. 12:98–104.

    Article  CAS  PubMed  Google Scholar 

  • Drayton, S., J. Rowe, R. Jones, R. Vatcheva, D. Cuthbert-Heavens, J. Marshall, M. Fried, and G. Peters. 2003. Tumor suppressor p16INK4a determines sensitivity of human cells to transformation by cooperating cellular oncogenes. Cancer Cell. 4:301–310.

    Article  CAS  PubMed  Google Scholar 

  • Esteller, M., S. Tortola, M. Toyota, G. Capella, M.A. Peinado, S.B. Baylin, and J.G. Herman. 2000. Hypermethylation-associated inactivation of p14 ARF is independent of p16 INK4a methylation and p53 mutational status. Cancer Res. 60:129–133.

    CAS  PubMed  Google Scholar 

  • Eymin, B., L. Karayan, P. Séité, C. Brambilla, E. Brambilla, C.-J. Larsen, and S. Gazzéri. 2001. Human ARF binds E2F1 and inhibits its transcriptional activity. Oncogene. 20:1033–1041.

    CAS  PubMed  Google Scholar 

  • Falck, J., N. Mailand, R.G. Syljuåsen, J. Bartek, and J. Lukas. 2001. The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature. 410:842–847.

    Article  CAS  PubMed  Google Scholar 

  • Fatyol, K., and A.A. Szalay. 2001. The p14ARF tumor suppressor protein facilitates nucleolar sequestration of hypoxia-inducible factor-1α (HIF-1α) and inhibits HIF-1-mediated transcription. J. Biol. Chem. 276:28421–28429.

    Article  CAS  PubMed  Google Scholar 

  • Felsher, D.W., and J.M. Bishop. 1999. Transient excess of MYC activity can elicit genomic instability and tumorigenesis. Proc. Natl. Acad. Sci. USA. 96:3940–3944.

    Article  CAS  PubMed  Google Scholar 

  • Ferbeyre, G., E. de Stanchina, E. Querido, N. Baptiste, C. Prives, and S.W. Lowe. 2000. PML is induced by oncogenic ras and promotes premature senescence. Genes Dev. 14:2015–2027.

    CAS  PubMed  Google Scholar 

  • Foster, S.A., D.J. Wong, M.T. Barrett, and D.A. Galloway. 1998. Inactivation of p16 in human mammary epithelial cells by CpG island methylation. Mol. Cell. Biol. 18:1793–1801.

    CAS  PubMed  Google Scholar 

  • Gil, J., D. Bernard, D. Martinez, and D. Beach. 2004. Polycomb CBX7 has a unifying role in cellular lifespan. Nature Cell Biol. 6:67–72.

    Article  CAS  PubMed  Google Scholar 

  • Gilley, J., and M. Fried. 2001. One INK4 gene and no ARF at the Fugu equivalent of the human INK4A/ARF/INK4B tumour suppressor locus. Oncogene. 20:7447–7452.

    Article  CAS  PubMed  Google Scholar 

  • Gorbunova, V., A. Seluanov, and O.M. Pereira-Smith. 2002. Expression of human telomerase (hTERT) does not prevent stress-induced senescence in normal human fibroblasts but protects the cells from stress-induced apoptosis and necrosis. J. Biol. Chem. 277:38540–38549.

    Article  CAS  PubMed  Google Scholar 

  • Haq, R., J.D. Brenton, M. Takahashi, D. Finan, R. Rottapel, and B. Zanke. 2002. Constitutive p38HOG mitogen-activated protein kinase activation induces permanent cell cycle arrest and senescence. Cancer Res. 62:5067–5082.

    Google Scholar 

  • Hara, E., R. Smith, D. Parry, H. Tahara, S. Stone, and G. Peters. 1996. Regulation of p16CDKN2 expression and its implications for cell immortalization and senescence. Mol. Cell. Biol. 16:859–867.

    CAS  PubMed  Google Scholar 

  • Harley, C.B. 1991. Telomere loss: mitotic clock or genetic time bomb? Mutat. Res. 256:271–282.

    CAS  PubMed  Google Scholar 

  • Hayflick, L. 1965. The limited in vitro lifespan of human diploid cell strains. Exp. Cell Res. 37:614–636.

    Article  CAS  PubMed  Google Scholar 

  • Herbig, U., W.A. Jobling, B.P.C. Chen, D.J. Chen, and J.M. Sedivy. 2004. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and 21CIP1, but not p16INK4a. Mol. Cell. 14:501–513.

    Article  CAS  PubMed  Google Scholar 

  • Hewitt, C., C.L. Wu, G. Evans, A. Howell, R.G. Elles, R. Jordan, P. Sloan, A.P. Read, and N. Thakker. 2002. Germline mutation of ARF in a melanoma kindred. Hum. Mol. Genet. 11:1273–1279.

    Article  CAS  PubMed  Google Scholar 

  • Hirai, H., M.F. Roussel, J.-Y. Kato, R.A. Ashmun, and C.J. Sherr. 1995. Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6. Mol. Cell. Biol. 15:2672–2681.

    CAS  PubMed  Google Scholar 

  • Honda, R., and H. Yasuda. 1999. Association of p19ARF with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumour suppressor p53. EMBO J. 18:22–27.

    Article  CAS  PubMed  Google Scholar 

  • Huot, T.J., J. Rowe, M. Harland, S. Drayton, S. Brookes, C. Goopta, P. Purkis, M. Fried, V. Bataille, E. Hara, J. Newton-Bishop, and G. Peters. 2002. Biallelic mutations in p16INK4a confer resistance to Ras-and Ets-induced senescence in human diploid fibroblasts. Mol. Cell. Biol. 22:8135–8143.

    Article  CAS  PubMed  Google Scholar 

  • Huschtscha, L.I., J.R. Noble, A.A. Neumann, E.L. Moy, P. Barry, J.R. Melki, S.J. Clark, and R.R. Reddel. 1998. Loss of p16INK4 expression by methylation is associated with lifespan extension of human mammary epithelial cells. Cancer Res. 58:3508–3512.

    CAS  PubMed  Google Scholar 

  • Itahana, K., K.P. Bhat, A. Jin, Y. Itahana, D. Hawke, R. Kobayashi, and Y. Zhang. 2003a. Tumor suppressor ARF degrades B23, a nucleolar protein involved in ribosome biogenesis and cell proliferation. Mol. Cell. 12:1151–1164.

    Article  CAS  PubMed  Google Scholar 

  • Itahana, K., Y. Zou, Y. Itahana, J.-L. Martinez, C. Beausejour, J.J.L. Jacobs, M. van Lohuizen, V. Band, J. Campisi, and G.P. Dimri. 2003b. Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1. Mol. Cell. Biol. 23:389–401.

    Article  CAS  PubMed  Google Scholar 

  • Iwasa, H., J. Han, and F. Ishikawa. 2003. Mitogen-activated protein kinase p38 defines the common senescence-signalling pathway. Genes to Cells. 8:131–144.

    Article  CAS  PubMed  Google Scholar 

  • Jacobs, J. J.L., P. Keblusek, E. Robanus-Maandag, P. Kristel, M. Lingbeek, P.M. Nederlof, T. van Welsem, M.J. van de Vijver, E.Y. Koh, G.Q. Daley, and M. van Lohuizen. 2000. Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19 ARF) and is amplified in a subset of human breast cancers. Nature Genet. 291:291–299.

    Google Scholar 

  • Jacobs, J.J.L., K. Kieboom, S. Marino, R.A. DePinho, and M. van Lohuizen. 1999. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature. 397:164–168.

    CAS  PubMed  Google Scholar 

  • Jiang, H., H.S. Chou, and L. Zhu. 1998. Requirement of cyclin E-Cdk2 inhibition in p16INK4a-mediated growth suppression. Mol. Cell. Biol. 18:5284–5290.

    CAS  PubMed  Google Scholar 

  • Kamijo, T., S. Bodner, E. van de Kamp, D.H. Randle, and C.J. Sherr. 1999a. Tumor spectrum in ARF-deficient mice. Cancer Res. 59:2217–2222.

    CAS  PubMed  Google Scholar 

  • Kamijo, T., E. van de Kamp, M.J. Chong, F. Zindy, J.A. Diehl, C.J. Sherr, and P.J. McKinnon. 1999b. Loss of ARF tumor suppressor reverses premature replicative arrest but not radiation hypersensitivity arising from disabled Atm function. Cancer Res. 59:2464–2469.

    CAS  PubMed  Google Scholar 

  • Kamijo, T., J.D. Weber, G. Zambetti, F. Zindy, M.F. Roussel, and C.J. Sherr. 1998. Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc. Natl. Acad. Sci. USA. 95:8292–8297.

    Article  CAS  PubMed  Google Scholar 

  • Kamijo, T., F. Zindy, M.F. Roussel, D.E. Quelle, J.R. Downing, R.A. Ashmun, G. Grosveld, and C.J. Sherr. 1997. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell. 91:649–659.

    Article  CAS  PubMed  Google Scholar 

  • Karayan, L., J.-F. Riou, P. Séité, J. Migeon, A. Cantereau, and C.-J. Larsen. 2001. Human ARF protein interacts with topoisomerase I and stimulates its activity. Oncogene. 20:836–848.

    Article  CAS  PubMed  Google Scholar 

  • Kashuba, E., K. Mattson, G. Klein, and L. Szekely. 2004. p14ARF induces the relocation of HDM2 and p53 to extranucleolar sites that are targeted by PML bodies and proteasomes. Mol. Cancer. 2:18.

    Google Scholar 

  • Kazianis, S., D.C. Morizot, L. Della Coletta, D.A. Johnston, B. Woolcock, J.R. Vielkind, and R.S. Nairn. 1999. Comparative structure and characterization of a CDKN2 gene in a Xiphophorus fish melanoma model. Oncogene. 18:5088–5099.

    Article  CAS  PubMed  Google Scholar 

  • Khan, S., C. Guevara, G. Fujii, and D. Parry. 2004. p14ARF is a component of the p53 response following ionizing irradiation of normal human fibroblasts. Oncogene. 23:6040–6046.

    Article  CAS  PubMed  Google Scholar 

  • Khan, S.H., J. Moritsugu, and G.M. Wahl. 2000. Differential requirement for p19ARF in the p53-dependent arrest induced by DNA damage, microtubule disruption, and ribonucloetide depletion. Proc. Natl. Acad. Sci. USA. 97:3266–3271.

    CAS  PubMed  Google Scholar 

  • Kim, S.-H., M. Mitchell, H. Fujii, S. Llanos, and G. Peters. 2003. Absence of p16INK4a and truncation of ARF tumor suppressors in chickens. Proc. Natl. Acad. Sci. USA. 100:211–216.

    CAS  PubMed  Google Scholar 

  • Kiyono, T., S.A. Foster, J.I. Koop, J.K. McDougall, D.A. Galloway, and A.J. Klingelhutz. 1998. Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature. 396:84–88.

    CAS  PubMed  Google Scholar 

  • Korgaonkar, C., L. Zhao, M. Modestou, and D.E. Quelle. 2002. ARF function does not require p53 stabilization or Mdm2 relocalization. Mol. Cell. Biol. 22:196–206.

    Article  CAS  PubMed  Google Scholar 

  • Kozar, K., M.A. Ciemerych, V.I. Rebel, H. Shigematsu, A. Zagozdzon, E. Sicinska, Y. Geng, Q. Yu, S. Batthacharya, R.T. Bronson, K. Akashi, and P. Sicinski. 2004. Mouse development and cell proliferation in the absence of D-cyclins. Cell. 118:477–491.

    Article  CAS  PubMed  Google Scholar 

  • Krimpenfort, P., K.C. Quon, W.J. Mool, A. Loonstra, and A. Berns. 2001. Loss of p16 Ink4a confers susceptibility to metastatic melanoma in mice. Nature. 413:83–86.

    Article  CAS  PubMed  Google Scholar 

  • Kuo, M.-L., W. den Besten, D. Bertwistle, M.F. Roussel, and C.J. Sherr. 2004. N-terminal polyubiquitination and degradation of the Arf tumor suppressor. Genes & Dev. 18:1862–1874.

    CAS  Google Scholar 

  • Li, Y., M.A. Nichols, J.W. Shay, and Y. Xiong. 1994. Transcriptional repression of the D-type cyclin-dependent kinase inhibitor p16 by the retinoblastoma susceptibility gene product pRb. Cancer Res. 54:6078–6082.

    CAS  PubMed  Google Scholar 

  • Li, Y., D. Wu, B. Chen, A. Ingram, L. He, L. Liu, D. Zhu, A. Kapoor, and D. Tang. 2004. ATM activity contributes to the tumor-suppressing functions of p14ARF. Oncogene. 23:7355–7365.

    CAS  PubMed  Google Scholar 

  • Lin, A.W., and S.W. Lowe. 2001. Oncogenic ras activates the ARF-p53 pathway to suppress epthelial cell transformation. Proc. Natl. Acad. Sci. USA. 98:5025–5030.

    CAS  PubMed  Google Scholar 

  • Lin, W.-C., F.-T. Lin, and J.R. Nevins. 2001. Selective induction of E2F1 in response to DNA damage, mediated by ATM-dependent phosphorylation. Genes Dev. 15:1833–1844.

    CAS  PubMed  Google Scholar 

  • Lindström, M.S., U. Klangby, R. Inoue, P. Pisa, K.G. Wiman, and C.E. Asker. 2000. Immunolocalization of human p14ARF to the granular component of the interphase nucleus. Exp. Cell Res. 256:400–410.

    PubMed  Google Scholar 

  • Llanos, S., P.A. Clark, J. Rowe, and G. Peters. 2001. Stabilisation of p53 by p14ARF without relocation of MDM2 to the nucleolus. Nature Cell Biol. 3:445–452.

    Article  CAS  PubMed  Google Scholar 

  • Lohrum, M. A.E., M. Ashcroft, M.H.G. Kubbutat, and K.H. Vousden. 2000a. Contribution of two independent MDM2-binding domains in p14ARF to p53 stabilization. Curr. Biol. 10:539–542.

    Article  CAS  PubMed  Google Scholar 

  • Lohrum, M.A.E., M. Ashcroft, M.H.G. Kubbutat, and K.H. Vousden. 2000b. Identification of a cryptic nucleolar-localization signal in MDM2. Nature Cell Biol. 2:179–181.

    CAS  PubMed  Google Scholar 

  • Lomazzi, M., M.C. Moroni, M.R. Jensen, E. Frittoli, and K. Helin. 2002. Suppression of the p53-or pRB-mediated G1 checkpoint is required for E2F-induced S-phase entry. Nat. Genet. 31:190–194.

    Article  CAS  PubMed  Google Scholar 

  • Lund, A.H., and M. van Lohuizen. 2004. Polycomb complexes and silencing mechanisms. Curr. Opin. Cell Biol. 16:239–246.

    Article  CAS  PubMed  Google Scholar 

  • Malumbres, M., R. Sotillo, D. Santamaria, J. Galan, A. Cerezo, S. Ortega, P. Dubus, and M. Barbacid. 2004. Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell. 118:493–504.

    Article  CAS  PubMed  Google Scholar 

  • Martelli, F., T. Hamilton, D.P. Silver, N.E. Sharpless, N. Bardeesy, M. Rokas, R.A. DePinho, D.M. Livingston, and S.R. Grossman. 2001. p19ARF targets certain E2F species for degradation. Proc. Natl. Acad. Sci. USA. 8:4455–4460.

    Google Scholar 

  • Masutomi, K., E.Y. Yu, S. Khurts, I. Ben-Porath, J.L. Currier, G.B. Metz, M.W. Brooks, S. Kaneko, S. Murakami, J.A. DeCaprio, R.A. Weinberg, S.A. Stewart, and W.C. Hahn. 2003. Telomerase maintains telomere structure in normal human cells. Cell. 114:241–253.

    Article  CAS  PubMed  Google Scholar 

  • Maya, R., M. Balass, S.-T. Kim, D. Shkedy, J.-F.M. Leal, O. Shifman, M. Moas, T. Buschmann, Z. Ronai, Y. Shiloh, M.B. Kastan, E. Katzir, and M. Oren. 2001. ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Genes & Dev. 15:1067–1077.

    CAS  Google Scholar 

  • McConnell, B.B., F.J. Gregory, F.J. Stott, E. Hara, and G. Peters. 1999. Induced expression of p16INK4a inhibits both CDK4-and CDK2-associated kinase activity by reassortment of cyclin-CDK-inhibitor complexes. Mol. Cell. Biol. 19:1981–1989.

    CAS  PubMed  Google Scholar 

  • Medema, R.H., R. Klompmaker, V.A.J. Smits, and G. Rijksen. 1998. p21waf1 can block cells at two points in the cell cycle, but does not interfere with processive DNA-replication or stress-activated kinases. Oncogene. 16:431–441.

    Article  CAS  PubMed  Google Scholar 

  • Michael, D., and M. Oren. 2003. The p53-Mdm2 module and the ubiquitin system. Sem. Cancer Biol. 13:49–58.

    CAS  Google Scholar 

  • Midgley, C.A., J.M.P. Desterro, M.K. Saville, S. Howard, A. Sparks, R.T. Hay, and D.P. Lane. 2000. An N-terminal p14ARFpeptide blocks Mdm2-dependent ubiquitination in vitro and can activate p53 in vivo. Oncogene. 19:2312–2323.

    Article  CAS  PubMed  Google Scholar 

  • Modestou, M., V. Puig-Antich, C. Korgaonkar, A. Eapen, and D.E. Quelle. 2001. The alternative reading frame tumor suppressor inhibits growth through p21-dependent and p21-independent pathways. Cancer Res. 61:3145–3150.

    CAS  PubMed  Google Scholar 

  • Morales, C.P., S.E. Holt, M. Ouellette, K.J. Kaur, Y. Yan, K.S. Wilson, M.A. White, W.E. Wright, and J.W. Shay. 1999. Absence of cancer-associated changes in human fibroblasts immortalized with telomerase. Nat. Genet. 21:115–118.

    Article  CAS  PubMed  Google Scholar 

  • Morris, M., P. Hepburn, and D. Wynford-Thomas. 2002. Sequential extension of proliferative lifespan in human fibroblasts induced by over-expression of CDK4 or 6 and loss of p53 function. Oncogene. 21:4277–4288.

    Article  CAS  PubMed  Google Scholar 

  • Munro, J., N.I. Barr, H. Ireland, V. Morrison, and E.K. Parkinson. 2004. Histone deacetylase inhibitors induce a senescence-like state in human cells by a p16-dependent mechanism that is independent of a mitotic clock. Exp. Cell Res. 295:528–538.

    Article  CAS  Google Scholar 

  • Munro, J., F.J. Stott, K.H. Vousden, G. Peters, and E.K. Parkinson. 1999. Role of the alternative INK4A proteins in human keratinocyte senescence: evidence for the specific inactivation of p16 INK4A upon immortalization. Cancer Res. 59:2516–2521.

    CAS  PubMed  Google Scholar 

  • Naka, K., A. Tachibana, K. Ikeda, and N. Motoyama. 2004. Stress-induced premature senescence in hTERT-expressing Ataxia-telangiectasia fibroblasts. J. Biol. Chem. 279:2030–2037.

    CAS  PubMed  Google Scholar 

  • Newbold, R.F., and R.W. Overell. 1983. Fibroblast immortality is a prerequisite for transformation by EJ c-Ha-ras oncogene. Nature. 304:648–651.

    Article  CAS  PubMed  Google Scholar 

  • Niculescu III, A.B., X. Chen, M. Smeets, L. Hengst, C. Prives, and S.I. Reed. 1998. Effects of p21Cip1/Waf1 at both the G1/S and the G2/M cell cycle transitions: pRb is a critical determinant in blocking DNA replication and in preventing endoreduplication. Mol. Cell. Biol. 18:629–643.

    CAS  PubMed  Google Scholar 

  • Ogryzko, V.V., T.H. Hirai, V.R. Russanova, D.A. Barbie, and B.H. Howard. 1996. Human fibroblast commitment to a senescence-like state in response to histone deacetylase inhibitors is cell cycle dependent. Mol. Cell. Biol. 16:5210–5218.

    CAS  PubMed  Google Scholar 

  • Ortega, S., I. Prieto, J. Odajima, A. Martin, P. Dubus, R. Sotillo, J.L. Barbero, M. Malumbres, and M. Barbacid. 2003. Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nat. Genet. 35:25–31.

    Article  CAS  PubMed  Google Scholar 

  • Parisi, T., A. Pollice, A. Di Cristofano, V. Calabrò, and G. La Mantia. 2002. Transcriptional regulation of the human tumor suppressor p14ARF by E2F1, E2F2, E2F3, and Sp1-like factors. Biochem. Biophys. Res. Commun. 291:1138–1145.

    Article  CAS  PubMed  Google Scholar 

  • Parrinello, S., E. Samper, A. Krtolica, J. Goldstein, S. Melov, and J. Campisi. 2003. Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat. Cell. Biol. 5:741–747.

    Article  CAS  PubMed  Google Scholar 

  • Parry, D., S. Bates, D.J. Mann, and G. Peters. 1995. Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product. EMBO J. 14:503–511.

    CAS  PubMed  Google Scholar 

  • Pollice, A., V. Nasti, R. Ronca, M. Vivo, M. Lo Iacono, R. Calogero, V. Calabrò, and G. La Mantia. Functional and physical interaction of the human ARF tumor suppressor with Tatbinding protein-1. J. Biol. Chem. 279:6345–6353.

    Google Scholar 

  • Pomerantz, J., N. Schreiber-Agus, N.J. Liégeois, A. Silverman, L. Alland, L. Chin, J. Potes, K. Chen, I. Orlow, H.-W. Lee, C. Cordon-Cardo, and R.A. DePinho. 1998. The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2’s inhibition of p53. Cell. 92:713–723.

    Article  CAS  PubMed  Google Scholar 

  • Qi, Y., M.A. Gregory, Z. Li, J.P. Brousal, K. West, and S.R. Hann. 2004. p19ARF directly and differentially controls the functions of c-Myc independently of p53. Nature.

    Google Scholar 

  • Quelle, D.E., M. Cheng, R.A. Ashmun, and C.J. Sherr. 1997. Cancer-associated mutations at the INK4a locus cancel cell cycle arrest by p16INK4a but not by the alternative reading frame protein p19ARF. Proc. Natl. Acad. Sci. USA. 94:669–673.

    Article  CAS  PubMed  Google Scholar 

  • Quelle, D.E., F. Zindy, R.A. Ashmun, and C.J. Sherr. 1995. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell. 83:993–1000.

    CAS  PubMed  Google Scholar 

  • Ramirez, R.D., C.P. Morales, B.-S. Herbert, J.M. Rohde, C. Passons, J.W. Shay, and W.E. Wright. 2001. Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions. Genes Dev. 15:398–403.

    Article  CAS  PubMed  Google Scholar 

  • Randerson-Moor, J.A., M. Harland, S. Williams, D. Cuthbert-Heavens, E. Sheridan, J. Aveyard, K. Sibley, L. Whitaker, M. Knowles, J. Newton Bishop, and D.T. Bishop. 2001. A germline deletion of p14ARF but not CDKN2A in a melanoma-neural system tumour syndrome family. Hum. Mol. Genet. 10:55–62.

    Article  CAS  PubMed  Google Scholar 

  • Rangarajan, A., and R.A. Weinberg. 2003. Comparative biology of mouse versus human cells: modelling human cancer in mice. Nat Rev. Cancer. 3:952–959.

    Article  CAS  PubMed  Google Scholar 

  • Rizos, H., A.P. Darmanian, G.J. Mann, and R.F. Kefford. 2000. Two arginine rich domains in the p14ARF tumour suppressor mediate nucleolar localization. Oncogene. 19:2978–2985.

    Article  CAS  PubMed  Google Scholar 

  • Robertson, K.D., and P.A. Jones. 1998. 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.

    CAS  PubMed  Google Scholar 

  • Robles, S.J., and G.R. Adami. 1998. Agents that cause DNA double strand breaks lead to p16INK4a enrichment and the premature senescence of normal fibroblasts. Oncogene. 16:1113–1123.

    Article  CAS  PubMed  Google Scholar 

  • Rodway, H., S. Llanos, J. Rowe, and G. Peters. 2004. Stability of nucleolar versus non-nucleolar forms of human p14ARF. Oncogene. 23:6186–6192.

    Article  CAS  PubMed  Google Scholar 

  • Ruas, M., and G. Peters. 1998. The p16INK4a/CDKN2A tumor suppressor and its relatives. Biochim. Biophys. Acta. 1378:115–177.

    Google Scholar 

  • Rubbi, C.P., and J. Milner. 2003. Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses. EMBO J. 22:6068–6077.

    CAS  PubMed  Google Scholar 

  • Russell, J.L., J.T. Powers, R.J. Rounbehler, P.M. Rogers, C.J. Conti, and D.G. Johnson. 2002. ARF differentially modulates apoptosis induced by E2F1 and Myc. Mol. Cell. Biol. 22:1360–1368.

    CAS  PubMed  Google Scholar 

  • Serrano, M., G.J. Hannon, and D. Beach. 1993. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 366:704–707.

    Article  CAS  PubMed  Google Scholar 

  • Serrano, M., A.W. Lin, M.E. McCurrach, D. Beach, and S.W. Lowe. 1997. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 88:593–602.

    Article  CAS  PubMed  Google Scholar 

  • Sharpless, N.E., N. Bardeesy, K.-H. Lee, D. Carrasco, D.H. Castrillon, A.J. Aguirre, E.A. Wu, J.W. Horner, and R.A. DePinho. 2001. Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature. 413:86–91.

    Article  CAS  PubMed  Google Scholar 

  • Sharpless, N.E., and R.A. DePinho. 1999. The INK4A/ARF locus and its two gene products. Curr. Opin. Genet. Dev. 9:22–30.

    Article  CAS  PubMed  Google Scholar 

  • Sherr, C.J. 2001. The INK4a/ARF network in tumour suppression. Nature Reviews. 2:731–737.

    CAS  PubMed  Google Scholar 

  • Sherr, C.J., and R.A. DePinho. 2000. Cellular senescence: mitotic clock or culture shock? Cell. 102:407–410.

    Article  CAS  PubMed  Google Scholar 

  • Sherr, C.J., and F. McCormick. 2002. The RB and p53 pathways in cancer. Cancer Cell. 2:103–112.

    Article  CAS  PubMed  Google Scholar 

  • Smogorzewska, A., and T. de Lange. 2002. Different telomere damage signaling pathways in human and mouse cells. EMBO J. 21:4338–4348.

    Article  CAS  PubMed  Google Scholar 

  • Soucek, T., O. Pusch, E. Hengstschläger-Ottnad, E. Wawra, G. Bernaschek, and M. Hengstschläger. 1995. Expression of the cyclin-dependent kinase inhibitor p16 during the ongoing cell cycle. FEBS Lett. 373:164–169.

    Article  CAS  PubMed  Google Scholar 

  • Stein, G.H., L.F. Drullinger, A. Soulard, and V. Dulic. 1999. Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. Mol. Cell. Biol. 19:2109–2117.

    CAS  PubMed  Google Scholar 

  • Stone, S., P. Jiang, P. Dayanath, S.V. Tavtigian, H. Katcher, D. Parry, G. Peters, and A. Kamb. 1995. Complex structure and regulation of the P16 (MTS1) locus. Cancer Res. 55:2988–2994.

    CAS  PubMed  Google Scholar 

  • Stott, F.J., S. Bates, M.C. James, B.B. McConnell, M. Starborg, S. Brookes, I. Palmero, E. Hara, K.H. Vousden, and G. Peters. 1998. The alternative product from the human CDKN2A locus, p14ARF, participates in a regulatory feedback loop with p53 and MDM2. EMBO J. 17:5001–5014.

    Article  CAS  PubMed  Google Scholar 

  • Sugihara, T., S.C. Kaul, J. Kato, R.R. Reddel, H. Nomura, and R. Wadhwa. 2001. Pex19p dampens the p19ARF-p53-p21WAF1 tumor suppressor pathway. J. Biol. Chem. 276:18649–18652.

    CAS  PubMed  Google Scholar 

  • Sugimoto, M., M.-L. Kuo, M.F. Roussel, and C.J. Sherr. 2003. Nucleolar Arf tumor suppressor inhibits ribosomal RNA processing. Mol. Cell. 11:415–424.

    Article  CAS  PubMed  Google Scholar 

  • Takekawa, M., M. Adachi, A. Nakahata, I. Nakayama, F. Itoh, H. Tsukuda, Y. Taya, and K. Imai. 2000. p53-inducible Wip1 phosphatase mediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation. EMBO J. 19:6517–6526.

    Article  CAS  PubMed  Google Scholar 

  • Tam, S.W., J.W. Shay, and M. Pagano. 1994. Differential expression and cell cycle regulation of the cyclin-dependent kinase 4 inhibitor p16Ink4. Cancer Res. 54:5816–5820.

    CAS  PubMed  Google Scholar 

  • Tao, W., and A.J. Levine. 1999. P19ARF stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2. Proc. Natl. Acad. Sci. USA. 96:6937–6941.

    CAS  PubMed  Google Scholar 

  • Vafa, O., M. Wade, S. Kern, M. Beeche, T.K. Pandita, G.M. Hampton, and G.M. Wahl. 2002. c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability. Mol. Cell. 9:1031–1044.

    Article  CAS  PubMed  Google Scholar 

  • van Lohuizen, M., S. Verbeek, B. Scheijen, E. Wientjens, H. van der Gulden, and B. A. 1991. Identification of cooperating oncogenes in Eμ-myc transgenic mice. Cell. 65:737–752.

    PubMed  Google Scholar 

  • Vaziri, H., and S. Benchimol. 1998. Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative lifespan. Curr. Biol. 8:279–282.

    Article  CAS  PubMed  Google Scholar 

  • Vivo, M., R.A. Calogero, F. Sansone, V. Calabro, T. Parisi, L. Borrelli, S. Saviozzi, and G. La Mantia. 2001. The human tumor suppressor ARF interacts with spinophilin/neurabin II, a type 1 protein-phosphatase-binding protein. J. Biol. Chem. 276:14161–14169.

    CAS  PubMed  Google Scholar 

  • Voorhoeve, M., and R. Agami. 2003. The tumor-suppressive functions of the human INK4A locus. Cancer Cell. 4:311–319.

    Article  CAS  PubMed  Google Scholar 

  • Wang, W., J.X. Chen, R. Liao, Q. Deng, J.J. Zhou, S. Huang, and P. Sun. 2002. Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence. Mol. Cell. Biol. 22:3389–3403.

    PubMed  Google Scholar 

  • Wang, X.-F., C.H. McGowan, M. Zhao, L. He, J.S. Downey, C. Fearns, Y. Wang, S. Huang, and J. Han. 2000. Involvement of the MKK6-p38γ cascade in γ-radiation-induced cell cycle arrest. Mol. Cell. Biol. 20:4543–4552.

    CAS  PubMed  Google Scholar 

  • Wang, X.Q., B.G. Gabrielli, A. Milligan, J.L. Dickinson, T.M. Antalis, and K.A.O. Ellem. 1996. Accumulation of p16CDKN2A in response to ultraviolet irradiation correlates with a late S-G2-phase cell cycle delay. Cancer Res. 56:2510–2514.

    CAS  PubMed  Google Scholar 

  • Weber, H.O., T. Samuel, P. Rauch, and J.O. Funk. 2002. Human p14ARF-mediated cell cycle arrest strictly depends on intact p53 signaling pathways. Oncogene. 21:3207–3212.

    Article  CAS  PubMed  Google Scholar 

  • Weber, J.D., J.R. Jeffers, J.E. Rehg, D.H. Randle, G. Lozano, M.F. Roussel, C.J. Sherr, and G.P. Zambetti. 2000a. p53-independent functions of the p19ARF tumor suppressor. Genes Dev. 14:2358–2365.

    Article  CAS  PubMed  Google Scholar 

  • Weber, J.D., M.-L. Kuo, B. Bothner, E.L. DiGiammarino, R.W. Kriwacki, M.F. Roussel, and C.J. Sherr. 2000b. Cooperative signals governing ARF-MDM2 interaction and nucleolar localization of the complex. Mol. Cell. Biol. 20:2517–2528.

    Article  CAS  PubMed  Google Scholar 

  • Weber, J.D., L.J. Taylor, M.F. Roussel, C.J. Sherr, and D. Bar-Sagi. 1999. Nucleolar Arf sequesters Mdm2 and activates p53. Nature Cell Biol. 1:20–26.

    CAS  PubMed  Google Scholar 

  • Wei, S., W. Wei, and J.M. Sedivy. 1999. Expression of catalytically active telomerase does not prevent premature senescence caused by overexpression of oncogenic Ha-Ras in normal human fibroblasts. Cancer Res. 59:1539–1543.

    CAS  PubMed  Google Scholar 

  • Wei, W., R.M. Hemmer, and J.M. Sedivy. 2001. The role of p14ARF in replicative and induced senescence of human fibroblasts. Mol. Cell. Biol. 21:6748–6757.

    CAS  PubMed  Google Scholar 

  • Wei, W., U. Herbig, A. Dutriaux, and J.M. Sedivy. 2003. Loss of retinoblastoma but not p16 function allows bypass of replicative senescence in human fibroblasts. Embo Rep. 4:1061–1066.

    Article  CAS  PubMed  Google Scholar 

  • Wright, W., and J.W. Shay. 2000. Telomere dynamics in cancer progression and prevention: fundamental differences in human and mouse telomere biology. Nature Med. 6:849–851.

    CAS  PubMed  Google Scholar 

  • Wright, W.E., and J.W. Shay. 2002. Historical claims and current interpretations of replicative aging. Nat. Biotechnol. 20:682–688.

    CAS  PubMed  Google Scholar 

  • Yarbrough, W.G., M. Bessho, A. Zanation, J.E. Bisi, and Y. Xiong. 2002. Human tumor suppressor ARF impedes S-phase progression independent of p53. Cancer Res. 62:1171–1177.

    CAS  PubMed  Google Scholar 

  • Zhang, Y., and Y. Xiong. 1999. Mutations in human ARF exon 2_disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and p53. Molec. Cell. 3:579–591.

    CAS  PubMed  Google Scholar 

  • Zhang, Y., Y. Xiong, and W.G. Yarbrough. 1998. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell. 92:725–734.

    CAS  PubMed  Google Scholar 

  • Zindy, F., C.M. Eischen, D.H. Randle, T. Kamijo, J.L. Cleveland, C.J. Sherr, and M.F. Roussel. 1998. Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev. 12:2424–2433.

    CAS  PubMed  Google Scholar 

  • Zindy, F., D.E. Quelle, M.F. Roussel, and C.J. Sherr. 1997. Expression of the p16INK4A tumor suppressor versus other INK4 family members during mouse development and aging. Oncogene. 15:203–211.

    Article  CAS  PubMed  Google Scholar 

  • Zindy, F., R.T. Williams, T.A. Baudino, J.E. Rehg, S.X. Skapek, J.L. Cleveland, M.F. Roussel, and C.J. Sherr. 2003. Arf tumor suppressor promoter monitors latent oncogenic signals in vivo. Proc. Natl. Acad. Sci. USA. 100:15930–15935.

    Article  CAS  PubMed  Google Scholar 

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del Gutierrez Arroyo, A., Peters, G. (2005). The INK4A/Arf Network — Cell Cycle Checkpoint or Emergency Brake?. In: Back, N., Cohen, I.R., Kritchevsky, D., Lajtha, A., Paoletti, R., Nigg, E.A. (eds) Genome Instability in Cancer Development. Advances in Experimental Medicine and Biology, vol 570. Springer, Dordrecht. https://doi.org/10.1007/1-4020-3764-3_8

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