Abstract
The G2 checkpoint prevents cells from entering mitosis when DNA is damaged, providing an opportunity for repair and stopping the proliferation of damaged cells. Because the G2 checkpoint helps to maintain genomic stability, it is an important focus in understanding the molecular causes of cancer. Many different methods have been used to investigate the G2 checkpoint and uncover some of the underlying mechanisms. Because cell cycle controls are highly conserved, a remarkable synergy between the genetic power of model organisms and biochemical analyses is possible and has uncovered control mechanisms that operate in many diverse species, including humans. CDC2, the cyclin-dependent kinase that normally drives cells into mitosis, is the ultimate target of pathways that mediate rapid arrest in G2 in response to DNA damage. Additional pathways ensure that the arrest is stably maintained. When mammalian cells contain damaged DNA, the p53 tumor suppressor and the Rb family of transcriptional repressors work together to downregulate a large number of genes that encode proteins required for G2 and M. Elimination of these essential cell cycle proteins helps to keep the cells arrested in G2.
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Hartwell, L. H., Culotti, J., Pringle, J. R. and Reid, B. J. (1974) Genetic control of the cell division cycle in yeast. Science 183, 46–51.
Nurse, P., Thuriaux, P. and Nasmyth, K. (1976) Genetic control of the cell division cycle in the fission yeast Schizosaccharomyces pombe. Mol. & Gen. Genet. 146, 167–178.
Beach, D., Durkacz, B. and Nurse, P. (1982) Functionally homologous cell cycle control genes in budding and fission yeast. Nature 300, 706–709.
Nurse, P. and Bissett, Y. (1981) Gene required in G1 for commitment to cell cycle and in G2 for control of mitosis in fission yeast. Nature 292, 558–560.
Nurse, P. and Thuriaux, P. (1980) Regulatory genes controlling mitosis in the fission yeast Schizosaccharomyces pombe. Genetics 96, 627–637.
Fantes, P. A. (1979) Eplstatic gene interactions in the control of division in fission yeast. Nature, 279, 428–430.
Nurse, P. (1975) Genetic control of cell size at cell division in yeast. Nature, 256, 547–551.
Russell, P. and Nurse, P. (1986) cdc25+ functions as an inducer in the mitotic control of fission yeast. Cell 45, 145–153.
Masui, Y. and Markert, C. L. (1971) Cytoplasmic control of nuclear behavior during meiotic maturation of frog oocytes. J. Exp. Zool., 177, 129–145.
Smith, L. D. and Ecker, R. E. (1971) The interaction of steroids with Rana pipiens oocytes in the induction of maturation. Dev. Biol. 25, 232–247.
Kishimoto, T. and Kanatani, H. (1976) Cytoplasmic factor responsible for germinal vesicle breakdown and meiotic maturation in starfish oocyte. Nature 260, 321–322.
Lohka, M. J. and Masui, Y. (1983) Formation in vitro of sperm pronuclei and mitotic chromosomes induced by amphibian ooplasmic components. Science 220, 719–721.
Lohka, M. J. and Maller, J. L. (1985) Induction of nuclear envelope breakdown, chromosome condensation, and spindle formation in cell-free extracts. J. Cell Biol. 101, 518–523.
Miake-Lye, R. and Kirschner, M. W. (1985) Induction of early mitotic events in a cell-free system. Cell 41, 165–175.
Lohka, M. J., Hayes, M. K., and Maller, J. L. (1988) Purification of maturation-promoting factor, an intracellular regulator of early mitotic events. Proc. Natl. Acad. Sci. USA 85, 3009–3013.
Labbe, J. C., Lee, M. G., Nurse, P., Picard, A., and Doree, M. (1988) Activation at M-phase of a protein kinase encoded by a starfish homologue of the cell cycle control gene cdc2+. Nature 335, 251–254.
Gautier, J., Norbury, C., Lohka, M., Nurse, P., and Maller, J. (1988) Purified maturation-promoting factor contains the product of aXenopus homolog of the fission yeast cell cycle control gene cdc2+. Cell 54, 433–439.
Arion, D., Meijer, L., Brizuela, L., and Beach, D. (1988) cdc2 is a component of the M phase-specific histone H1 kinase: evidence for identity with MPF. Cell 55, 371–378.
Dunphy, W. G., Brizuela, L., Beach, D., and Newport, J. (1988) The Xenopus cdc2 protein is a component of MPF, a cytoplasmic regulator of mitosis. Cell 54, 423–431.
Evans, T., Rosenthal, E. T., Youngblom, J., Distel, D., and Hunt, T. (1983) Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division. Cell 33, 389–396.
Swenson, K. I., Farrell, K. M., and Ruderman, J. V. (1986) The clam embryo protein cyclin A induces entry into M phase and the resumption of meiosis in Xenopus oocytes. Cell 47, 861–870.
Murray, A. W., Solomon, M. J., and Kirschner, M. W. (1989) The role of cyclin synthesis and degradation in the control of maturation promoting factor activity. Nature 339, 280–286.
Murray, A. W. and Kirschner, M. W. (1989) Cyclin synthesis drives the early embryonic cell cycle. Nature 339, 275–280.
Gautier, J., Minshull, J., Lohka, M., Glotzer, M., Hunt, T., and Maller, J. L. (1990) Cyclin is a component of maturation-promoting factor from Xenopus, Cell 60, 487–494.
Draetta, G., Luca, F., Westendorf, J., Brizuela, L., Ruderman, J., and Beach, D. (1989) Cdc2 protein kinase is complexed with both cyclin A and B: evidence for proteolytic inactivation of MPF. Cell 56, 829–838.
Hardie, D. G., Matthews, H. R., and Bradbury, E. M. (1976) Cell-cycle dependence of two nuclear histone kinase enzyme activities. Eur. J. Biochem. 66, 37–42.
Meijer, L. and Pondaven, P. (1988) Cyclic activation of histone H1 kinase during sea urchin egg mitotic divisions. Exp. Cell Res. 174, 116–129.
Picard, A., Peaucellier, G., le Bouffant, F., Le Peuch, C., and Doree, M. (1985) Role of protein synthesis and proteases in production and inactivation of maturation-promoting activity during meiotic maturation of starfish oocytes. Dev. Biol. 109, 311–320.
Cicirelli, M. F., Pelech, S. L., and Krebs, E. C. (1988) Activation of multiple protein kinases during the burst in protein phosphorylation that precedes the first mejotic cell division in Xenopus oocytes. J. Biol. Chem. 263, 2009–2019.
Lake, R. S., Goidl, J. A., and Salzman, N. P. (1972) F1-histone modification at metaphase in Chinese hamster cells. Exp. Cell Res. 73, 113–121.
Bradbury, E. M., Inglis, R. J., and Matthews, H. R. (1974) Control of cell division by very lysine rich histone (F1) phosphorylation. Nature 247, 257–261.
Pines, J. (1995) Cyclins and cyclin-dependent kinases: a biochemical view. Biochem. J. 308, 697–711.
Smits, V. A. and Medema, R. H. (2001) Checking out the G(2)/M transition. Biochim. Biophys. Acta 1519, 1–12.
Hagting, A., Karlsson, C., Clute, P., Jackman, M., and Pines, J. (1998) MPF localization is controlled by nuclear export. EMBO J. 17, 4127–4138.
Pines, J. and Hunter, T. (1991) Human cyclins A and B1 are differentially located in the cell and undergo cell cycle-dependent nuclear transport. J. Cell Biol. 115, 1–17.
Toyoshima, F., Moriguchi, T., Wada, A., Fukuda, M. and Nishida, E. (1998) Nuclear export of cyclin B1 and its possible role in the DNA damage- induced G2 checkpoint. EMBO J. 17, 2728–2735.
Yang, J., Bardes, E. S., Moore, J. D., Brennan, J., Powers, M. A., and Kornbluth, S. (1988) Control of cyclin B1 localization through regulated binding of the nuclear export factor CRM1. Genes & Dev. 12, 2131–2143.
Moore, J. D., Yang, J., Truant, R., and Kornbluth, S. (1999) Nuclear import of Cdk/cyclin complexes: identification of distinct mechanisms for import of Cdk2/cyclin E and Cdc2/cyclin B1. J. Cell Biol. 144, 213–224.
Takizawa, C. G., Weis, K., and Morgan, D. O. (1999) Ran-independent nuclear import of cyclin B1-Cdc2 by importin beta. Proc. Natl. Acad. Sci. U. S. A. 96 7938–7943.
Toyoshima-Morimoto, F., Taniguchi, E., Shinya, N., Iwamatsu, A., and Nishida, E. (2001) Polo-like kinase 1 phosphorylates cyclin B1 and targets it to the nucleus during prophase. Nature 410, 215–220.
Collyer, T., Hardy, C. F., and Yuan, J. (1999) Cooperative phosphorylation including the activity of polo-like kinase 1 regulates the subcellular localization of cyclin B1. Mol. Cell. Biol. 19, 4270–4278.
Borgne, A., Ostvold, A. C., Flament, S., and Meijer, L. (1999) Intra-M phase-promoting factor phosphorylation of cyclin B at the prophase/metaphase transition. J. Biol. Chem. 274, 11977–11986.
Poon, R. Y., Yamashita, K., Adamzewski, J. P., Hunt, T., and Shuttleworth, J. (1993) The cdc2-related protein p40M015 is the catalytic subunit of a protein kinase that can activate p33cdk 2 and p34cdc2. EMBO J. 12, 3123–3132.
Fesquet, D., Labbe, J. C., Derancourt, J., et al. (1993) The MO15 gene encodes the catalytic subunit of a protein kinase that activates cdc2 and other cyclin-dependent kinases (CDKs) through phosphorylation of Thr161 and its homologues. EMBO J. 12, 3111–3121.
Booher, R. N., Holman, P. S., and Fattaey, A. (1997) Human Myt1 is a cell cycle-regulated kinase that inhibits Cdc2 but not Cdk2 activity. J. Biol. Chem. 272, 22300–22306.
Liu, F., Stanton, J. J., Wu, Z., and Piwnica-Worms, H. (1997) The human Myt1 kinase preferentially phosphorylates Cdc2 on threonine 14 and localizes to the endoplasmic reticulum and Golgi complex. Mol. Cell. Biol. 17, 571–583.
Parker, L. L. and Piwnica-Worms, H. (1992) Inactivation of the p34cdc2-cyclin B complex by the human WEE1 tyrosine kinase. Science 257, 1955–1957.
Gould, K. L. and Nurse, P. (1989) Tyrosine phosphorylation of the fission yeast cdc2+protein kinase regulates entry into mitosis. Nature 342, 39–45.
Amon, A., Surana, U., Muroff, I., and Nasmyth, K. (1992) Regulation of p34CDC28 tyrosine phosphorylation is not required for entry into mitosis in S. cerevisiae. Nature 355, 368–371.
Sorger, P. K. and Murray, A. W. (1992) S-phase feedback control in budding yeast independent of tyrosine phosphorylation of p34cdc28. Nature 355, 365–368.
Draetta, G. and Eckstein, J. (1997) Cdc25 protein phosphatases in cell proliferations. Biochim. Biophys. Acta. 1332, M53-M63.
De Souza, C. P., Ellem, K. A., and Gabrielli, B. G. (2000) Centrosomal and cytoplasmic Cdc2/cyclin B1 activation precedes nuclear mitotic events. Exp. Cell Res. 257, 11–21.
Ferguson, A. M., White, L. S., Donovan, P. J. and Piwnica-Worms, H. (2005) Normal cell cycle and checkpoint responses in mice and cells lacking Cdc25B and Cdc25C protein phosphatases. Mol. Cell Biol. 25, 2853–2860.
Maity, A., McKenna, W. G., and Muschel, R. J. (1994) The molecular basis for cell cycle delays following ionizing radiation: a review. Radiotherapy & Oncology 31, 1–13.
Smith, K. A., Gorman, P. A., Stark, M. B., Groves, R. P., and Stark, G. R. (1990) Distinctive chromosomal structures are formed very early in the amplication of CAD genes in Syrian hamster cells. Cell 63, 1219–1227.
Xu, B., Kim, S. T., Lim, D. S., and Kastan, M. B. (2002) Two molecularly distinct G(2)/M checkpoints are induced by ionizing irradiation. Mol. Cell. Biol. 22, 1049–1059.
Van Vugt, M. A., Smits, V. A., Klompmaker, R., and Medema, R. H. (2001) Inhibition of Polo-like kinase-1 by DNA damage occurs in an ATM- or ATR-dependent fashion. J. Biol. Chem. 276, 41656–41660.
Taylor, W. R. (2003) FACS-based detection of phosphorylated histone H3 for the quantitation of mitotic cells. In Checkpoint Controls and Cancer: Methods and Protocols (Schonthal A. H., ed). Humana Press, Totowa, NJ.
Weinert, T. A. (1989) The RAD9 gene controls the cell cycle response to DNA damage in Saccharomyces cerevisiae. Science 246, 629–634.
O'Connell, M. J., Walworth, N. C., and Carr, A. M. (2000) The G2-phase DNA-damage checkpoint. Trends Cell Biol. 10, 296–303.
Lowndes, N. F. and Murguia, J. R. (2000) Sensing and responding to DNA damage. Curr. Opin. Gen. Dev. 10, 17–25.
Nyberg, K. A., Michelson, R. J., Putnam, C. W., and Weinert, T. A. (2002) Toward maintaining the genome: DNA damage and replication checkpoints. Ann. Rev. Genet. 36, 617–656.
Elledge S. J. (1996) Cell cycle checkpoints: preventing an identity crisis. Science 274, 1664–1672.
Lock, R. B. and Ross, W. E. (1990) Inhibition of p34cdc2 kinase activity by etoposide or irradiation as a mechanism of G2 arrest in Chinese hamster ovary cells. Cancer Res. 50, 3761–3766.
Kharbanda, S., Saleem, A., Datta, R., Yuan, Z. M., Weichselbaum, R., and Kufe, D. (1994) Ionizing radiation induces rapid tyrosine phosphorylation of p34cdc2. Cancer Res. 54, 1412–1414.
Furnari, B., Rhind, N., and Russell, P. (1997) Cdc25 mitotic inducer targeted by chk 1 DNA damage checkpoint kinase [see comments]. Science 277, 1495–1497.
Peng, C. Y., Graves, P. R., Thoma, R. S., Wu, Z., Shaw, A. S., and Piwnica-Worms, H. (1997) Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phasphorylation of Cdc25C on serine-216 [see comments]. Science 277, 1501–1505.
Sanchez, Y., Wong, C., Thoma, R. S., Richman, R., Wu, Z., Piwnica-Worms, H., and Elledge, S. J. (1997) Conservation of the Chk 1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25 [see comments]. Science 277, 1497–1501.
Walworth, N., Davey, S., and Beach, D. (1993) Fission yeast chk1 protein kinase links the rad checkpoint pathway to cdc2. Nature 363, 368–371.
Murakami, H. and Okayama, H. (1995) A kinase from fission yeast reponsible for blocking mitosis in S phase. Nature 374, 817–819.
McGowan, C. H. (2002) Checking in on Cds1 (Chk2): a checkpoint kinase and tumor suppressor. Bioessays 24, 502–511.
Chaturvedi, P., Eng, W. K., Zhu, Y., et al. (1999). Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway. Oncogene 18, 4047–4054.
Liu, Q., Guntuku, S., Cui, X. S., et al. (2000) Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes & Dev. 14, 1448–1459.
Matsuoka, S., Rotman, G., Ogawa, A., Shiloh, Y. Tamai, K., and Elledge, S. J. (2000) Ataxia telanglectasia-mutated phosphorylates chk2 in vivo and in vitro [In Process Citation]. Proc. Natl. Acad. Sci. USA 97, 10389–10394.
Abraham, R. T. (2001) Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes & Dev. 15, 2177–2196.
Banin, S., Moyal, L., Shieh, S., t al. (1998) Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 281, 1674–1677.
Canman, C. E., Lim, D. S., Cimpric, K. A., et al., (1998) Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 281, 1677–1679.
Siliciano, J. D., Canman, C. E., Taya, Y., Sakaguchi, K., Appella, E., and Kastan, M. B. (1997) DNA damage induces phosphorylation of the amino terminus of p53. Genes & Dev. 11, 3471–3481.
Cliby, W. A., Roberts, C. J., Cimprich, K. A., Stringer, C. M., Lamb, J. R., Schreiber, S. L., and Friend, S. H. (1998) Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoint. EMBO J. 17, 159–169.
Tibbetts, R. S., Brumbaugh, K. M., Williams, J. M., et al. (1999) A role for ATR in the DNA damageinduced phosphorylation of p53. Genes & Dev. 13, 152–157.
Savitsky, K., Bar-Shira, A., Gilad, S., et al. (1995) A single ataxia telangiectasia gene with a product simillar to PI-3 kinase. Science 268, 1749–1753
Bulavin, D. V., Higashimoto, Y., Popoff, I. J., et al. (2001) Intiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase. Nature 411, 102–107.
Baber-Furnari, B. A., Rhind, N., Boddy, M. N., Shanahan, P., Lopez-Girona, A., and Russell, P. (2000) Regulation of mitotic inhibitor Mik 1 helps to enforce the DNA damage checkpoint. Mol. Biol. Cell 11, 1–11.
Michael, W. M. and Newport, J. (1998) Coupling of mitosis to the completion of S phase through Cdc34-mediated degradation of Wee1. Science 282, 1886–1889.
Smits, V. A., Klompmaker, R., Arnaud, L., Rijksen, G., Nigg, E. A., and Medema, R. H. (2000) Polo-like kinase-1 is a target of the DNA damage checkpoint. Nat. Cell Biol. 2, 672–676.
Griffiths, D. J., Barbet, N. C., McCready, S., Lehmann, A. R., and Carr, A. M. (1995) Fission yeast rad17: a homologue of budding yeast RAD24 that shares regions of sequence similarity with DNA polymerase accessory proteins. EMBO J. 14, 5812–5923.
Green, C. M., Erdjument-Bromage, H., Tempst, P., and Lowndes, N. F. (2000) A novel Rad24 checkpoint protein complex closely related to replication factor C [erratum appears in Curr Biol 2000 Feb 24;10(4):R171] Curr. Biol. 10, 39–42.
St Onge, R. P., Udell, C. M., Casselman, R., and Davey, S. (1999) The human G2 checkpoint control protein hRAD9 is a nuclear phosphoprotein that forms complexes with hRAD1 and hHUS1. Mol. Biol. Cell 10, 1985–1995.
Lindsey-Boltz, L. A., Bermudez, V. P., Hurwitz, J., and Sancar, A. (2001) Purification and characterization of human DNA damage checkpoint Rad complexes. Proc. Natl. Acad. Sci. USA 98, 11236–11241
Venclovas, C. and Thelen, M. P. (2000) Structurebased predictions of Rad1, Rad9, Hus1 and Rad17 participation in sliding clamp and clamp-loading complexes. Nucleic Acids Res. 28, 2481–2493.
Walworth, N. C., and Bernards, R. (1996) rad-dependent response of the chk1-encoded protein kinase at the DNA damage checkpoint. Science 271, 353–356.
Parker, A. E., Van de Weyer, I., Laus, M. C., Oostveen, I., Yon, J., Verhasselt, P., and Luyten, W. H. (1998) A human homologue of the Schizosaccharomyces pombe rad1+checkpoint gene encodes an exonuclease. J. Biol. Chem. 273, 18332–18339.
Miki, Y., Swensen, J., Shattuck-Eidens, D., et al. (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266, 66–71.
Futreal, P. A., Liu, Q., Shattuck-Eidens, D., et al. (1994) BRCA1 mutations in primary breast and ovarian carcinomas. Science 266, 120–122.
Scully, R., Chen, J., Ochs, R. L., Keegan, K., Hoekstra, M., Feunteun, J., and Livingston, D. M. (1997) Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Cell 90, 425–435.
Wang, Y., Cortez, D., Yazdi, P., Neff, N., Elledge, S. J., and Qin, J. (2000) BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes & Dev. 14, 927–939
Dolganov, G., Maser, R., Novikov, A., Tosto, L., Chong, S., Bressan, D., and Petrini, J. (1996) Human Rad50 is physically associated with human Mre 11: identification of a conserved multiprotein complex implicated in recombinational DNA repair. Mol. Cell. Biol. 16, 4832–4841.
Maser, R., Monsen, K., Nelms B., and Petrini J. (1997) hMre11 and hRAd50 nuclear foci are induced during the normal cellular response to DNA double-strand breaks. Mol. Cell. Biol. 17, 6087–6096.
D'Amours, D. and Jackson, S. (2002) The Mre11 complex: at the crossroads of dna repair and check-point signalling. Nat. Rev. Mol. Cell Biol. 3, 317–327.
Edwards, R. J., Bentley, N. J., and Carr, A. M. (1999) A Rad3-Rad26 complex responds to DNA damage independently of other checkpoint proteins. Nat. Cell Biol. 1, 393–398.
Lopez-Girona, A., Tanaka, K., Chen, X. B., Baber, B. A., McGowan, C. H., and Russell, P. (2001) Serine-345 is required for Rad3-dependent phosphorylation and function of checkpoint kinase Chk1 in fission yeast. Proc. Natl. Acad. Sci. USA 98, 11289–11294.
Bakkenist C. and Kastan, M. (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation [In Process Citation]. Nature 421, 499–506.
Schultz, L., Chehab, N., Malikzay, A., and Halazonetis, T. (2000) p53 binding protein 1 (53BP1) is an early participant in the cellular response to DNA double-strand breaks. J. Cell Biol. 151, 1381–1390.
Wang, B., Matsuoka, S., Carpenter, P., and Elledge, S. (2002) 53S3BP1, a mediator of the DNA damage checkpoint. Science 298, 1435–1438.
Iwabuchi, K., Bartel, P., Li, B., Marraccino, R., and Fields, S. (1994) Two cellular proteins that bind to wild-type but not mutant p53. Proc. Natl. Acad. Sci. USA 91, 6098–6102.
Lee, J. H. and Paull, T. T. (2004) Direct activation of the ATM protein kinase by the Mre 11/Rad50/Nbs1 complex. Science 304, 93–96.
Uziel, T., Lerenthal, Y., Moyal, L., Andegeko, Y., Mittelman L., and Shiloh, Y. (2003) Requirement of the MRN complex for ATM activation by DNA damage. Embo J 22, 5612–5621.
Falck J., Coates, J., and Jackson, S. P. (2005) Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 434, 605–611.
Lane, D. P. and Crawford, L. V. (1979) T antigen is bound to a host protein in SV40-transformed cells. Nature 278, 261–263.
Lane, D. (1984) Cell immortalization and transformation by the p53 gene. Nature 312, 596–597.
Jenkins, J., Rudge, K., and Currie, G. (1984) Cellular immortalization by a cDNA clone encoding the transformation-associated phosphoprotein p53. Nature 312, 651–654.
Parada, L., Land, H., Weinberg, R., Wolf, D., and Rotter, V. (1984) Cooperation between gene encoding p53 tumour antigen and ras in cellular transformation. Nature 312, 649–651.
Eliyahu, D., Raz, A., Gruss, P., Givol, D., and Oren, M. (1984) Participation of p53 cellular tumour antigen in transformation of normal embryonic cells. Nature 312, 646–649.
Finlay, C., Hinds, P., Tan, T., Eliyahu, D., Oren, M., and Levine, A. (1988) Activating mutations for transformation by p53 produce a gene product that forms an hsc70-p53 complex with an altered half-life. Mol. Cell. Biol. 8, 531–539.
Fearon, E. and Vogelstein, B. (1990) A genetic model for colorectal tumorigenesis, Cell 61, 759–767.
Donehower, L. A., Harvey, M., Slagle, B. L., McArthur, M. J., Montgomery, C. A., Jr., Butel, J. S., and Bradley, A. (1992) Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215–221.
Greenblatt, M. S., Bennett, W. P., Hollstein, M., and Harris, C. C. (1994) Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 54, 4855–4878
Srivastava, S., Zou, Z., Pirollo, K., Blattner, W., and Chang, E. (1990) Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature 348, 747–749.
Malkin, D., Li, F., Strong, L., et al. (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250, 1233–1238.
Li, F. P. and Fraumeni, J. F. (1969) Rhabdomyosarcoma in children: an epidemiologic study and identification of a familial cancer syndrome. J. Nat. Cancer Inst. 43, 1364–1373.
Ko, L. J., and Prives, C. (1996) p53: puzzle and paradign. Genes & Dev. 10, 1054–1072.
Vogelstein, B., Lane, D., and Levine, A. J. (2000) Surfing the p53 network. Nature 408, 307–310.
Appella, E., and Anderson, C. W. (2001) Post-translational modifications and activation of p53 by genotoxic stresses. Eur. J. Biochem. 268, 2764–2772.
Momand, J., Wu, H. H., and Dasgupta, G. (2000) MDM2—master regulator of the p53 tumor suppressor protein. Gene 242, 15–29.
Chehab, N. H., Malikzay, A., Stavridi, E. S., and Halazonetis, T. D. (1999) Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage. Proc. Natl. Acad. Sci. USA 96, 13777–13782.
Hirao, A., Kong, Y. Y., Matsuoka, S., et al. (2000) DNA damage induced activation of p53 by the check-point kinase Chk2 [see comments]. Science 287, 1824–1827.
Shieh, S. Y., Ahn, J., Tamai, K., Taya, Y., and Prives, C. (2000) The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites [published erratum appears in Genes & Dev. 2000 Mar 15;14(6):750]. Genes & Dev. 14, 289–300.
Jallepalli, P. V., Lengauer, C., Vogelstein, B., and Bunz, F. (2003) The Chk2 tumor suppressor is not required for p53 responses in human cancer cells. J. Biol. Chem. 278, 20475–20579.
Ahn, J., Urist, M., and Prives, C. (2003) Questioning the role of checkpoint kinase 2 in the p53 DNA damage response. J. Biol. Chem. 278, 20480–20489.
Shieh, S. Y., Ikeda, M., Taya, Y., and Prives, C. (1997) DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell 91, 325–334.
Sakaguchi, K., Herrera, J. E., Saito, S., et al. (1998) DNA damage activates p53 through a phosphorylation-acetylation cascade. Genes & Dev. 12, 2831–2841.
Gu, W. and Roeder, R. G. (1997) Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90, 595–606.
Espinosa, J.M. and Emerson, B. M. (2001) Transcriptional regulation by p53 through intrinsic DNA/chromatin binding and site-directed cofactor recruitment. Mol. Cell 8, 67–69.
Maltzman W., and Czyzyk, L. (1984) UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells. Mol. Cell. Biol. 4, 1689–1694.
Kastan, M. B., Onyekwere, O., Sidransky, D., Vogelstein, B., and Craig, R. W. (1991) Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 51, 6304–6311.
Agarwal, M. L., Agarwal, A., Taylor, W. R., and Stark, G. R. (1995) p53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts. Proc. Natl. Acad. Sci. USA 92, 8493–8497.
Taylor, W. R. and Stark, G. R. (2001) Regulation of the G2/M transition by p53. Oncogene 20, 1803–1815.
Stewart, N., Hicks, G. G., Paraskevas, F., and Mowat, M. (1995) Evidence for a second cell cycle block at G2/M by p53. Oncogene 10, 109–115.
Taylor, W. R., DePrimo, S. E., Agarwal, A., Agarwal, M. L., Schonthal, A. H., Katula, K. S., and Stark, G. R. (1999) Mechanisms of G2 arrest in response to overexpression of p53. Mol. Biol. Cell. 10, 3607–3622.
Bunz, F., Dutriaux, A., Lengauer, C., et al. (1998) Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282, 1497–1501.
Harper, J. W., Elledge, S. J., Keyomarsi, K., et al.. (1995) Inhibition of cyclin-dependent kinases by p21. Mol. Biol. Cell. 6, 387–400.
Bates, S., Ryan, K. M., Phillips, A. C., and Vousden, K. H. (1998) Cell cycle arrest and DNA endoreduplication following p21 Waf1/Cip1 expression. Oncogene 17, 1691–1703.
Medema, R. H., Klompmaker, R., Smits, V. A., and Rijksen, G. (1998) P21 wafl 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.
Niculescu, A. B., 3rd, Chen, X., Smeets, M., Hengst, L., Prives, C., and Reed, S. I. (1998) Effects of p21(Cipl/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 [published erratum appears in Mol. Cell Biol. 1998 Mar; 18(3):1763]. Mol. Cell. Biol. 18, 629–643.
Smits, V. A., Klompmaker, R., Vallenius, T., Rijksen, G., Makela, T. P., and Medema, R. H. (2000) p2T inhibits thr161 phosphorylation of cdc2 to enforce the G2 DNA damage checkpoint [In Process Citation]. J. Biol. Chem. 275, 30638–30643.
Baus, F., Gire, V., Fisher, D., Piette, J., and Dulic, V. (2003) Permanent cell cycle exit in G2 phase after DNA damage in normal human fibroblasts. EMBO J. 22, 3992–4002.
Jin, S., Antinore, M. J., Lung, F. D., et al. (2000) The GADD45 inhibition of Cdc2 kinase correlates with GADD45-mediated growth suppression. J. Biol. Chem. 275, 16602–16608.
Zhan, Q., Antinore, M. J., Wang, X. W., Carrier, F., Smith, M. L., Harris, C. C., and Fornace, A. J., Jr. (1999) Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45. Oncogene 18, 2892–2900.
Wang, X. W., Zhan, Q., Coursen, J. D., et al. (1999) GADD45 induction of a G2/M cell cycle checkpoint. Proc. Natl. Acad. Sci. USA 96, 3706–3711.
Hermeking, H., Lengauer, C., Polyak, K., et al., (1997) 14-3-3 sigma is a p53-regulated inhibitor of G2/M progression. Mol. Cell 1, 3–11.
Chan, T. A., Hermeking, H., Lengauer, C., Kinzler, K. W., and Vogelstein, B. (1999) 14-3-3Sigma is required to prevent mitotic catastrophe after DNA damage [see comments]. Nature 401, 616–620.
Chan, T. A., Hwang, P. M., Hermeking, H., Kinzler, K. W., and Vogelstein, B. (2000) Cooperative effects of genes controlling the G(2)/M checkpoint. Genes & Dev. 14, 1584–1588.
Innocente, S. A., Abrahamson, J. L., Cogswell, J. P., and Lee, J. M. (1999) p53 regulates a G2 checkpoint through cyclin B1. Proc. Natl. Acad. Sci. USA 96, 2147–2152.
Lau, C. C. and Pardee, A. B. (1982) Mechanism by which caffeine potentiates lethality of nitrogen mustard. Proc. Natl. Acad. Sci. U. S. A. 79, 2942–2946.
Fan, S., Smith, M. L., Rivet, D. J., 2nd, et al. (1995) Disruption of p53 function sensitizes breast cancer MCF-7 cells to cisplatin and pentoxifylline. Cancer Res. 55, 1649–1654.
Clifford, B., Beljin, M., Stark, G. R., and Taylor, W. R. (2003) G2 arrest in response to topoisomerase II inhibitors: the role of p53. Cancer Res. 63, 4074–4081.
Blasina, A., Price, B. D., Turenne, G. A., and McGowan, C. H. (1999) Caffeine inhibits the checkpoint kinase ATM. Curr. Biol. 9, 1135–1138.
Sarkaria, J. N., Busby, E. C., Tibbetts, R. S., Roos, P., Taya, Y., Karnitz, L. M., and Abraham, R. T. (1999) Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, Caffeine. Cancer Res. 59, 4375–4382.
Zhou, B. B., Chaturvedi, P., Spring, K., et al. (2000) Caffeine abolishes the mammalian (G(2)/M (DNA damage checkpoint by inhibiting ataxia-telangiecta-sia-mutated kinase activity. J. Biol. Chem. 275, 10342–10348.
Kanda, T., Sullivan, K. F., and Wahl, G. M. (1998) Histone-GFP fusion protein enables sensitive analysis of chromosome dynamics in living mammalian cells. Curr. Biol. 8, 377–385.
Taylor, W. R., Schonthal, A. H., Galante, J., and Stark, G. R. (2001) p130/E2F4 binds to and represses the cdc2 promoter in response to p53. J. Biol. Chem. 276, 1998–2006.
Sugarman, J. L., Schonthal, A. H., and Glass, C. K. (1995) Identification of a cell-type-specific and E2F-independent mechanism for repression of cdc2 transcription. Mol. Cell. Biol. 15, 3282–3290.
Zwicker, J., Lucibello, F. C., Wolfraim, L. A., Gross, C., Truss, M., Engeland, K., and Muller, R. (1995) Cell cycle regulation of the cyclin A, cdc25C and cdc2 genes is based on a common mechanism of transcriptional repression. EMBO J. 14, 4514–4522.
Tommasi, S. and Pfeifer, G. P. (1995) In vivo structure of the human cdc2 promoter: release of a p130-E2F-4 complex from sequences immediately upstream of the transcription initiation site coincides with induction of cdc2 expression. Mol. Cell. Biol. 15, 6901–6913.
Kovesdi, I., Reichel, R., and Nevins, J. R. (1987) Role of an adenovirus E2 promoter binding factor in E1A-mediated coordinate gene control. Proc. Natl. Acad. Sci. USA 84, 2180–2184.
Trimarchi, J. M., and Lees, J. A. (2002) Sibling rivalry in the E2F family. Nat. Rev. Mol. Cell Biol. 3, 11–20.
Maiti, B., Li, J., de Bruin, C., et al. (2005) Cloning and characterization of mouse E2F8, a novel mammalian E2F family member capable of blocking cellular proliferation. J. Biol. Chem. 280, 18211–18220.
de Bruin, A., Maiti, B., Jakoi, L., Timmers, C., Buerki, R., and Leone, G. (2003) Identification and characterization of E2F7, a novel mammalian E2F family member capable of blocking cellular proliferation. J. Biol. Chem. 278, 42041–42049.
Di Stefano, L., Jensen, M. R., and Helin, K. (2003) E2F7, a novel E2F featuring DP-independent repression of a subset of E2F-regulated gene. EMBO J. 22, 6289–6298.
Friend, S. H., Bernards, R., Rogelj, S., Weinberg, R. A., Rapaport, J. M., Albert, D. M., and Dryja, T. P. (1986) A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323, 643–646.
Harbour, J. W. and Dean, D. C. (2000) Rb function in cell-cycle regulation and apoptosis. Nat. Cell. Biol. 2, E65-E67.
Lipinski, M. M. and Jacks, T. (1999) The retinoblastoma gene family in differentiation and development. Oncogene 18, 7873–7882.
Flatt, P. M., Tang, L. J., Scatena, C. D., Szak, S. T., and Pietenpol, J. A. (2000) p53 regulation of G(2) checkpoint is retinoblastoma protein dependent. Mol. Cell. Biol. 20, 4210–4223.
Polager, S. and Ginsberg, D. (2003) E2F mediates sustained G2 arrest and down-regulation of Stathmin and AIM-1 expression in response to genotoxic stress. J. Biol. Chem. 278, 1443–1449.
Jackson, M. W., Agarwal, M. K., Yang, J., et al. (2005) P130/p107/p105Rb-dependent transcriptional repression during DNA-damage-induced cell-cycle exit at G2. J. Cell Sci. 118, 1821–1832
Dou, Q P., Zhao, S., Levin, A. H., Wang, J., Helin, K., and Pardee, A. B. (1994) G1/S-regulated E2F-containing protein complexes bind to the mouse thymidine kinase gene promoter. J. Biol. Chem. 269, 1306–1313.
Ishida, S., Huang, E., Zuzan, H., Spang, R., Leone, G., West, M., and Nevins, J. R. (2001) Role for E2F in control of both DNA replication and mitotic functions as revealed from DNA microarray analysis. Mol. Cell. Biol. 21, 4684–4699.
Polager, S., Kalma, Y., Berkovich, E., and Ginsberg, D. (2002) E2Fs up-regulate expression of genes involved in DNA replication, DNA repair and mitosis. Oncogene 21, 437–446.
Ren, B., Cam, H., Takahashi, Y., Volkert, T., Terragni, J., Young, R. A., and Dynlacht, B. D. (2002) E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. Genes & Dev. 16, 245–256.
Chang, B. D., Broude, E. V., Fang, J. V. K. T., Abdryashitov, R., Poole, J. C., and Roninson, I. B. (2000) p21 Waf1/Cip1/Sdi1-induced growth arrest is associated with depletion of mitosis-control proteins and leads to abnormal mitosis and endoreduplication in recovering cells. Oncogene 19, 2165–2170.