Full Text:   <4512>

CLC number: R73

On-line Access: 2024-08-27

Received: 2023-10-17

Revision Accepted: 2024-05-08

Crosschecked: 0000-00-00

Cited: 37

Clicked: 8600

Citations:  Bibtex RefMan EndNote GB/T7714

-   Go to

Article info.
1. Reference List
Open peer comments

Journal of Zhejiang University SCIENCE B 2007 Vol.8 No.6 P.377-397

http://doi.org/10.1631/jzus.2007.B0377


DNA-damage response network at the crossroads of cell-cycle checkpoints, cellular senescence and apoptosis


Author(s):  SCHMITT Estelle, PAQUET Claudie, BEAUCHEMIN Myriam, BERTRAND Richard

Affiliation(s):  Notre Dame Hospital and Montreal Cancer Institute, Research Centre of University of Montreal Hospital Centre (CRCHUM), Montreal (Que) H2L 4M1, Canada; more

Corresponding email(s):   richard.bertrand@umontreal.ca

Key Words:  DNA-damage response network, Cell cycle, Cellular senescence, Apoptosis, Bcl-2 family


Share this article to: More |Next Article >>>

SCHMITT Estelle, PAQUET Claudie, BEAUCHEMIN Myriam, BERTRAND Richard. DNA-damage response network at the crossroads of cell-cycle checkpoints, cellular senescence and apoptosis[J]. Journal of Zhejiang University Science B, 2007, 8(6): 377-397.

@article{title="DNA-damage response network at the crossroads of cell-cycle checkpoints, cellular senescence and apoptosis",
author="SCHMITT Estelle, PAQUET Claudie, BEAUCHEMIN Myriam, BERTRAND Richard",
journal="Journal of Zhejiang University Science B",
volume="8",
number="6",
pages="377-397",
year="2007",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.2007.B0377"
}

%0 Journal Article
%T DNA-damage response network at the crossroads of cell-cycle checkpoints, cellular senescence and apoptosis
%A SCHMITT Estelle
%A PAQUET Claudie
%A BEAUCHEMIN Myriam
%A BERTRAND Richard
%J Journal of Zhejiang University SCIENCE B
%V 8
%N 6
%P 377-397
%@ 1673-1581
%D 2007
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.2007.B0377

TY - JOUR
T1 - DNA-damage response network at the crossroads of cell-cycle checkpoints, cellular senescence and apoptosis
A1 - SCHMITT Estelle
A1 - PAQUET Claudie
A1 - BEAUCHEMIN Myriam
A1 - BERTRAND Richard
J0 - Journal of Zhejiang University Science B
VL - 8
IS - 6
SP - 377
EP - 397
%@ 1673-1581
Y1 - 2007
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.2007.B0377


Abstract: 
Tissue homeostasis requires a carefully-orchestrated balance between cell proliferation, cellular senescence and cell death. Cells proliferate through a cell cycle that is tightly regulated by cyclin-dependent kinase activities. cellular senescence is a safeguard program limiting the proliferative competence of cells in living organisms. apoptosis eliminates unwanted cells by the coordinated activity of gene products that regulate and effect cell death. The intimate link between the cell cycle, cellular senescence, apoptosis regulation, cancer development and tumor responses to cancer treatment has become eminently apparent. Extensive research on tumor suppressor genes, oncogenes, the cell cycle and apoptosis regulatory genes has revealed how the DNA damage-sensing and -signaling pathways, referred to as the DNA-damage response network, are tied to cell proliferation, cell-cycle arrest, cellular senescence and apoptosis. DNA-damage responses are complex, involving “sensor” proteins that sense the damage, and transmit signals to “transducer” proteins, which, in turn, convey the signals to numerous “effector” proteins implicated in specific cellular pathways, including DNA repair mechanisms, cell-cycle checkpoints, cellular senescence and apoptosis. The bcl-2 family of proteins stands among the most crucial regulators of apoptosis and performs vital functions in deciding whether a cell will live or die after cancer chemotherapy and irradiation. In addition, several studies have now revealed that members of the bcl-2 family also interface with the cell cycle, DNA repair/recombination and cellular senescence, effects that are generally distinct from their function in apoptosis. In this review, we report progress in understanding the molecular networks that regulate cell-cycle checkpoints, cellular senescence and apoptosis after DNA damage, and discuss the influence of some bcl-2 family members on cell-cycle checkpoint regulation.

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

Reference

[1] Adams, J.M., Cory, S., 2001. Life-or-death decisions by the Bcl-2 protein family. Trends Biochem. Sci., 26(1):61-66.

[2] Adams, J.M., Cory, S., 2007. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene, 26(9):1324-1337.

[3] Agami, R., Blandino, G., Oren, M., Shaul, Y., 1999. Interaction of c-Abl and p73α and their collaboration to induce apoptosis. Nature, 399(6738):809-813.

[4] Aguda, B.D., 1999. A quantitative analysis of the kinetics of the G(2) DNA damage checkpoint system. Proc. Natl. Acad. Sci. (USA), 96(20):11352-11357.

[5] Antonsson, B., Conti, F., Ciavatta, A., Montessuit, S., Lewis, S., Martinou, I., Bernasconi, L., Bernard, A., Mermod, J.J., Mazzei, G., et al., 1997. Inhibition of Bax channel-forming activity by Bcl-2. Science, 277(5324):370-372.

[6] Antonsson, B., Montessuit, S., Lauper, S., Eskes, R., Martinou, J.C., 2000. Bax oligomerization is required for channel-forming activity in liposomes and to trigger cytochrome c release from mitochondria. Biochem. J., 345(2):271-278.

[7] Bae, J., Leo, C.P., Hsu, S.Y., Hsueh, A.J., 2000. Mcl-1S, a splicing variant of the antiapoptotic Bcl-2 family member Mcl-1, encodes a proapoptotic protein possessing only the BH3 domain. J. Biol. Chem., 275(33):25255-25261.

[8] Bakkenist, C.J., Kastan, M.B., 2004. Initiating cellular stress responses. Cell, 118(1):9-17.

[9] Bartkova, J., Rezaei, N., Liontos, M., Karakaidos, P., Kletsas, D., Issaeva, N., Vassiliou, L.V., Kolettas, E., Niforou, K., Zoumpourlis, V.C., et al., 2006. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature, 444(7119):633-637.

[10] Basañez, G., Nechushtan, A., Drozhinin, O., Chanturiya, A., Choe, E., Tutt, S., Wood, K.A., Hsu, Y., Zimmerberg, J., Youle, R.J., 1999. Bax, but not Bcl-xL, decreases the lifetime of planar phospholipid bilayer membranes at subnanomolar concentrations. Proc. Natl. Acad. Sci. (USA), 96(10):5492-5497.

[11] Bergamaschi, D., Gasco, M., Hiller, L., Sullivan, A., Syed, N., Trigiante, G., Yulug, I., Merlano, M., Numico, G., Comino, A., et al., 2003. p53 polymorphism influences response in cancer chemotherapy via modulation of p73-dependent apoptosis. Cancer Cell, 3(4):387-402.

[12] Bernardi, P., Scorrano, L., Colonna, R., Petronilli, V., Di Lisa, F., 1999. Mitochondria and cell death. Mechanistic aspects and methodological issues. Eur. J. Biochem., 264(3):687-701.

[13] Bertrand, R., Sarang, M., Jenkin, J., Kerrigan, D., Pommier, Y., 1991. Differential induction of secondary DNA fragmentation by topoisomerase II inhibitors in human tumor cell lines with amplified c-myc expression. Cancer Res., 51:6280-6285.

[14] Bertrand, R., Solary, E., Jenkins, J., Pommier, Y., 1993. Apoptosis and its modulation in human promyelocytic HL-60 cells treated with DNA topoisomerase I and II inhibitors. Exp. Cell Res., 207(2):388-397.

[15] Bingle, C.D., Craig, R.W., Swales, B.M., Singleton, V., Zhou, P., Whyte, M.K., 2000. Exon skipping in Mcl-1 results in a bcl-2 homology domain 3 only gene product that promotes cell death. J. Biol. Chem., 275(29):22136-22146.

[16] Blagosklonny, M.V., Schulte, T., Nguyen, P., Trepel, J., Neckers, L.M., 1996. Taxol-induced apoptosis and phosphorylation of Bcl-2 protein involves c-Raf-1 and represents a novel c-Raf-1 signal transduction pathway. Cancer Res., 56:1851-1854.

[17] Blagosklonny, M.V., Giannakakou, P., el Deiry, W.S., Kingston, D.G., Higgs, P.I., Neckers, L., Fojo, T., 1997. Raf-1/Bcl-2 phosphorylation: a step from microtubule damage to cell death. Cancer Res., 57:130-135.

[18] Boise, L.H., Gonzalez-Garcia, M., Postema, C.E., Ding, L., Lindsten, T., Turka, L.A., Mao, X., Nunez, G., Thompson, C.B., 1993. Bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell, 74(4):597-608.

[19] Booher, R.N., Holman, P.S., Fattaey, A., 1997. Human Myt1 is a cell cycle-regulated kinase that inhibits Cdc2 but not Cdk2 activity. J. Biol. Chem., 272(35):22300-22306.

[20] Borgne, A., Meijer, L., 1996. Sequential dephosphorylation of p34cdc2 on Thr-14 and Tyr-15 at the prophase/metaphase transition. J. Biol. Chem., 271(44):27847-27854.

[21] Borner, C., 1996. Diminished cell proliferation associated with the death-protective activity of Bcl-2. J. Biol. Chem., 271:12695-12698.

[22] Borner, C., Martinou, I., Mattmann, C., Irmler, M., Schaerer, E., Martinou, J.C., Tschopp, J., 1994. The protein bcl-2 alpha does not require membrane attachment, but two conserved domains to suppress apoptosis. J. Cell. Biol., 126(4):1059-1068.

[23] Bossy-Wetzel, E., Newmeyer, D.D., Green, D.R., 1998. Mitochondrial cytochrome C release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization. EMBO J., 17(1):37-49.

[24] Boyd, J., Malstrom, S., Subramanian, T., Venkatesh, L.K., Schaeper, U., Elangovan, B., D'Sa-Eipper, C., Chinnadurai, G., 1994. E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins. Cell, 79(2):341-351.

[25] Boyd, J.M., Gallo, G.J., Elangovan, B., Houghton, A.B., Malstrom, S., Avery, B.J., Ebb, R.G., Subramanian, T., Chittenden, T., Lutz, R.J., et al., 1995. Bik, a novel death-inducing protein shares a distinct sequence motif with Bcl-2 family proteins and interacts with viral and cellular survival-promoting proteins. Oncogene, 11:1921-1928.

[26] Brady, H.J.M., Gil-Gómez, G., Kirberg, J., Berns, A.J.M., 1996. Bax-a perturbs T cell development and affects cell cycle entry of T cells. EMBO J., 15:6991-7001.

[27] Brown, A.L., Lee, C.H., Schwarz, J.K., Mitiku, N., Piwnica-Worms, H., Chung, J.H., 1999. A human Cds1-related kinase that functions downstream of ATM protein in the cellular response to DNA damage. Proc. Natl. Acad. Sci. (USA), 96(7):3745-3750.

[28] Bunz, F., Dutriaux, A., Lengauer, C., Waldman, T., Zhou, S., Brown, J.P., Sedivy, J.M., Kinzler, K.W., Vogelstein, B., 1998. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science, 282(5393):1497-1501.

[29] Campisi, J., 2001. Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol., 11(11):S27-S31.

[30] Cazales, M., Schmitt, E., Montembault, E., Dozier, C., Prigent, C., Ducommun, B., 2005. CDC25B phosphorylation by Aurora-A occurs at the G2/M transition and is inhibited by DNA damage. Cell Cycle, 4:1233-1238.

[31] Chang, B.S., Minn, A.J., Muchmore, S.W., Fesik, S.W., Thompson, C.B., 1997. Identification of a novel regulatory domain in Bcl-X(L) and Bcl-2. EMBO J., 16(5):968-977.

[32] Chang, B.D., Broude, E.V., Dokmanovic, M., Zhu, H., Ruth, A., Xuan, Y., Kandel, E.S., Lausch, E., Christov, K., Roninson, I.B., 1999a. A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents. Cancer Res., 59:3761-3767.

[33] Chang, B.D., Xuan, Y., Broude, E.V., Zhu, H., Schott, B., Fang, J., Roninson, I.B., 1999b. Role of p53 and p21waf1/cip1 in senescence-like terminal proliferation arrest induced in human tumor cells by chemotherapeutic drugs. Oncogene, 18(34):4808-4818.

[34] Chao, D.T., Korsmeyer, S.J., 1998. Bcl-2 family: regulators of cell death. Annu. Rev. Immunol., 16(1):395-419.

[35] Chautan, M., Chazal, G., Cecconi, F., Gruss, P., Golstein, P., 1999. Interdigital cell death can occur through a necrotic and caspase-independent pathway. Curr. Biol., 9(17):967-970.

[36] Chen, G., Cizeau, J., Vande Velde, C., Park, J.H., Bozek, G., Bolton, J., Shi, L., Dubik, D., Greenberg, A., 1999. Nix and Nip3 form a subfamily of pro-apoptotic mitochondrial proteins. J. Biol. Chem., 274(1):7-10.

[37] Chen, L., Willis, S.N., Wei, A., Smith, B.J., Fletcher, J.I., Hinds, M.G., Colman, P.M., Day, C.L., Adams, J.M., Huang, D.C., 2005. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol. Cell, 17(3):393-403.

[38] Chipuk, J.E., Kuwana, T., Bouchier-Hayes, L., Droin, N.M., Newmeyer, D.D., Schuler, M., Green, D.R., 2004. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science, 303(5660):1010-1014.

[39] Chipuk, J.E., Bouchier-Hayes, L., Kuwana, T., Newmeyer, D.D., Green, D.R., 2005. Puma couples the nuclear and cytoplasmic proapoptotic function of p53. Science, 309(5741):1732-1735.

[40] Chittenden, T., 2002. BH3 domains: intracellular death-ligands critical for initiating apoptosis. Cancer Cell, 2(3):165-166.

[41] Chittenden, T., Harrington, E.A., O'Connor, R., Flemington, C., Lutz, R.J., Evan, G.I., Guild, B.C., 1995a. Induction of apoptosis by the Bcl-2 homologue Bak. Nature, 374(6524):733-736.

[42] Chittenden, T., Flemington, C., Houghton, A.B., Ebb, R.G., Gallo, G.J., Elangovan, B., Chinnadurai, G., Lutz, R.J., 1995b. A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions. EMBO J., 14:5589-5596.

[43] Choi, S.S., Park, I.C., Yun, J.W., Sung, Y.C., Hong, S.I., Shin, H.S., 1995. A novel Bcl-2 related gene, Bfl-1, is overexpressed in stomach cancer and preferentially expressed in bone marrow. Oncogene, 11:1693-1698.

[44] Chou, J.J., Li, H., Salvesen, G.S., Yuan, J., Wagner, G., 1999. Solution structure of BID, an intracellular amplifier of apoptotic signaling. Cell, 96(5):615-624.

[45] Chu, Z.L., McKinsey, T.A., Liu, L., Gentry, J.J., Malim, M.H., Ballard, D.W., 1997. Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis C-Iap2 is under NF-kappa-B control. Proc. Natl. Acad. Sci. (USA), 94(19):10057-10062.

[46] Cleary, M.L., Smith, S.D., Sklar, J., 1986. Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell, 47(1):19-28.

[47] Cliby, W.A., Lewis, K.A., Lilly, K.K., Kaufmann, S.H., 2002. S phase and G2 arrests induced by topoisomerase I poisons are dependent on ATR kinase function. J. Biol. Chem., 277(2):1599-1606.

[48] Cory, S., Adams, J.M., 2002. The bcl2 family: regulators of the cellular life-or-death switch. Nat. Rev. Cancer, 2(9):647-656.

[49] Costanzo, A., Merlo, P., Pediconi, N., Fulco, M., Sartorelli, V., Cole, P.A., Fontemaggi, G., Fanciulli, M., Schiltz, L., Blandino, G., Balsano, C., Levrero, M., 2002. DNA damage-dependent acetylation of p73 dictates the selective activation of apoptotic target genes. Mol. Cell, 9(1):175-186.

[50] Crompton, M., 1999. The mitochondrial permeability transition pore and its role in cell death. Biochem. J., 341(2):233-249.

[51] d'Adda di Fagagna, F., Reaper, P.M., Clay-Farrace, L., Fiegler, H., Carr, P., von Zglinicki, T., Saretzki, G., Carter, N.P., Jackson, S.P., 2003. A DNA damage checkpoint response in telomere-initiated senescence. Nature, 426(6963):194-198.

[52] Das, R., Reddy, E.P., Chatterjee, D., Andrews, D.W., 1996. Identification of a novel Bcl-2 related gene, Brag-1, in human glioma. Oncogene, 12:947-951.

[53] Desagher, S., Martinou, J.C., 2000. Mitochondria as the central control point of apoptosis. Trends Cell Biol., 10(9):369-377.

[54] Di Leonardo, A., Linke, S.P., Clarkin, K., Wahl, G.M., 1994. DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes. Dev., 8:2540-2551.

[55] Di Micco, R., Fumagalli, M., Cicalese, A., Piccinin, S., Gasparini, P., Luise, C., Schurra, C., Garre, M., Nuciforo, P.G., Bensimon, A., et al., 2006. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature, 444(7119):638-642.

[56] Diaz, J.L., Oltersdorf, T., Horne, W., McConnell, M., Wilson, G., Weeks, S., Garcia, T., Fritz, L.C., 1997. A common binding site mediates heterodimerization and homodimerization of Bcl-2 family members. J. Biol. Chem., 272(17):11350-11355.

[57] Domen, J., Cheshier, S.H., Weissman, I.L., 2000. The role of apoptosis in the regulation of hematopoietic stem cells. Overexpression of bcl-2 increases both their number and repopulation potential. J. Exp. Med., 191(2):253-264.

[58] Domina, A.M., Smith, J.H., Craig, R.W., 2000. Myeloid cell leukemia 1 is phosphorylated through two distinct pathways, one associated with extracellular signal-regulated kinase activation and the other with G2/M accumulation or protein phosphatase 1/2A inhibition. J. Biol. Chem., 275(28):21688-21694.

[59] Draetta, G., Beach, D., 1988. Activation of cdc2 protein kinase during mitosis in human cells: cell cycle-dependent phosphorylation and subunit rearrangement. Cell, 54(1):17-26.

[60] Draetta, G., Luca, F., Westendorf, J., Brizuela, L., Ruderman, J., Beach, D., 1989. Cdc2 protein kinase is complexed with both cyclin A and B: evidence for proteolytic inactivation of MPF. Cell, 56(5):829-838.

[61] Droin, N., Dubrez, L., Eymin, B., Renvoize, C., Breard, J., Dimanche-Boitrel, M.T., Solary, E., 1998. Upregulation of Casp genes in human tumor cells undergoing etoposide-induced apoptosis. Oncogene, 16(22):2885-2894.

[62] Du, C., Fang, M., Li, Y., Li, L., Wang, X., 2000. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell, 102(1):33-42.

[63] Dubrez, L., Goldwasser, F., Genne, P., Pommier, Y., Solary, E., 1995. The role of cell cycle regulation and apoptosis triggering in determining the sensitivity of leukemic cells to topoisomerase I and II inhibitors. Leukemia, 9:1013-1024.

[64] Dubrez, L., Savoy, I., Hamman, A., Solary, E., 1996. Pivotal role of a DEVD-sensitive step in etoposide-induced and Fas-mediated apoptotic pathways. EMBO J., 15:5504-5512.

[65] Ducommun, B., Brambilla, P., Felix, M.A., Franza, B.R.Jr, Karsenti, E., Draetta, G., 1991. Cdc2 phosphorylation is required for its interaction with cyclin. EMBO J., 10:3311-3319.

[66] Dumont, P., Leu, J.I., Della Pietra, A.C., George, D.L., Murphy, M., 2003. The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat. Genet., 33(3):357-365.

[67] Epand, R.F., Martinou, J.C., Fornallaz-Mulhauser, M., Hughes, D.W., Epand, R.M., 2002. The apoptotic protein tBid promotes leakage by altering membrane curvature. J. Biol. Chem., 277(36):32632-32639.

[68] Falck, J., Mailand, N., Syljuasen, R.G., Bartek, J., Lukas, J., 2001. The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature, 410(6830):842-847.

[69] Fan, M., Du, C., Stone, A.A., Gilbert, K.M., Chambers, T.C., 2000a. Modulation of mitogen-activated protein kinases and phosphorylation of Bcl-2 by vinblastine represent persistent forms of normal fluctuations at G2-M. Cancer Res., 60:6403-6407.

[70] Fan, M., Goodwin, M., Vu, T., Brantley-Finley, C., Gaarde, W.A., Chambers, T.C., 2000b. Vinblastine-induced phosphorylation of Bcl-2 and Bcl-XL is mediated by JNK and occurs in parallel with inactivation of the Raf-1/MEK/ERK cascade. J. Biol. Chem., 275(39):29980-29985.

[71] Fang, G.F., Chang, B.S., Kim, C.N., Perkins, C., Thompson, C.B., Bhalla, K.N., 1998. Loop domain is necessary for taxol-induced mobility shift and phosphorylation of Bcl-2 as well as for inhibiting taxol-induced cytosolic accumulation of cytochrome c and apoptosis. Cancer Res., 58:3202-3208.

[72] Farrow, S.N., White, J.H., Martinou, I., Raven, T., Pun, K.T., Grinham, C.J., Martinou, J.C., Brown, R., 1995. Cloning of a bcl-2 homologue by interaction with adenovirus E1B 19K. Nature, 374(6524):731-733.

[73] Flatten, K., Dai, N.T., Vroman, B.T., Loegering, D., Erlichman, C., Karnitz, L.M., Kaufmann, S.H., 2005. The role of checkpoint kinase 1 in sensitivity to topoisomerase I poisons. J. Biol. Chem., 280(14):14349-14355.

[74] Flores, E.R., Tsai, K.Y., Crowley, D., Sengupta, S., Yang, A., McKeon, F., Jacks, T., 2002. p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature, 416(6880):560-564.

[75] Fontemaggi, G., Kela, I., Amariglio, N., Rechavi, G., Krishnamurthy, J., Strano, S., Sacchi, A., Givol, D., Blandino, G., 2002. Identification of direct p73 target genes combining DNA microarray and chromatin immunoprecipitation analyses. J. Biol. Chem., 277(45):43359-43368.

[76] Foo, S.Y., Nolan, G.P., 1999. NF-kappaB to the rescue: RELs, apoptosis and cellular transformation. Trends Genet., 15(6):229-235.

[77] Freebern, W.J., Smith, J.L., Chaudhry, S.S., Haggerty, C.M., Gardner, K., 2003. Novel cell-specific and dominant negative anti-apoptotic roles of p73 in transformed leukemia cells. J. Biol. Chem., 278(4):2249-2255.

[78] Fujise, K., Zhang, D., Liu, J., Yeh, E.T., 2000. Regulation of apoptosis and cell cycle progression by MCL1. Differential role of proliferating cell nuclear antigen. J. Biol. Chem., 275(50):39458-39465.

[79] Furnari, B., Rhind, N., Russell, P., 1997. Cdc25 mitotic inducer targeted by Chk1 DNA damage checkpoint kinase. Science, 277(5331):1495-1497.

[80] Furnari, B., Blasina, A., Boddy, M.N., McGowan, C.H., Russell, P., 1999. Cdc25 inhibited in vivo and in vitro by checkpoint kinases Cds1 and Chk1. Mol. Biol. Cell, 10:833-845.

[81] Gibson, L., Holmgreen, S.P., Huang, D.C.S., Bernard, O., Copeland, N.G., Jenkins, N.A., Sutherland, G.R., Baker, E., Adams, J.M., Cory, S., 1996. Bcl-W, a novel member of the Bcl-2 family, promotes cell survival. Oncogene, 13:665-675.

[82] Gillardon, F., Moll, I., Meyer, M., Michaelidis, T.M., 1999. Alterations in cell death and cell cycle progression in the UV-irradiated epidermis of bcl-2-deficient mice. Cell Death Differ., 6(1):55-60.

[83] Gong, J.G., Costanzo, A., Yang, H.Q., Melino, G., Kaelin, W.G.Jr, Levrero, M., Wang, J.Y., 1999. The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature, 399(6738):806-809.

[84] Gottlieb, T.M., Oren, M., 1998. p53 and apoptosis. Semin. Cancer Biol., 8(5):359-368.

[85] Gottlieb, R.A., Nordberg, J., Skowronski, E., Babior, B.M., 1996. Apoptosis induced in Jurkat cells by several agents is preceded by intracellular acidification. Proc. Natl. Acad. Sci. (USA), 93(2):654-658.

[86] Gross, A., Jockel, J., Wei, M.C., Korsmeyer, S.J., 1998. Enforced dimerization of Bax results in its translocation, mitochondrial dysfunction and apoptosis. EMBO J., 17(14):3878-3885.

[87] Grumont, R.J., Rourke, I.J., O'Reilly, L.A., Strasser, A., Miyake, K., Sha, W., Gerondakis, S., 1998. B lymphocytes differentially use the Rel and nuclear factor kappa-B1 (NF-kappa-B1) transcription factors to regulate cell cycle progression and apoptosis in quiescent and mitogen-activated cells. J. Exp. Med., 187(5):663-674.

[88] Guney, I., Sedivy, J.M., 2006. Cellular senescence, epigenetic switches and c-Myc. Cell Cycle, 5:2319-2323.

[89] Guo, B., Godzik, A., Reed, J.C., 2001. Bcl-G, a novel pro-apoptotic member of the bcl-2 family. J. Biol. Chem., 276(4):2780-2785.

[90] Gupta, M., Fan, S.J., Zhan, Q.M., Kohn, K.W., O'Connor, P.M., Pommier, Y., 1997. Inactivation of p53 increases the cytotoxicity of camptothecin in human colon HCT116 and breast MCF-7 cancer cells. Clin. Cancer Res., 3:1653-1660.

[91] Haldar, S., Jena, N., Croce, C.M., 1995. Inactivation of Bcl-2 by phosphorylation. Proc. Natl. Acad. Sci. (USA), 92(10):4507-4511.

[92] Haldar, S., Chintapalli, J., Croce, C.M., 1996. Taxol induces Bcl-2 phosphorylation and death of prostate cancer cells. Cancer Res., 56:1253-1255.

[93] Haldar, S., Basu, A., Croce, C.M., 1998. Serine-70 is one of the critical sites for drug-induced Bcl2 phosphorylation in cancer cells. Cancer Res., 58:1609-1615.

[94] Han, J., Sabbatini, P., White, E., 1996. Induction of apoptosis by human Nbk/Bik, a BH3-containing protein that interacts with E1b 19k. Mol. Cell Biol., 16:5857-5864.

[95] Han, J., Flemington, C., Houghton, A.B., Gu, Z., Zambetti, G.P., Lutz, R.J., Zhu, L., Chittenden, T., 2001. Expression of Bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals. Proc. Natl. Acad. Sci. (USA), 98(20):11318-11323.

[96] Han, Z., Wei, W., Dunaway, S., Darnowski, J.W., Calabresi, P., Sedivy, J., Hendrickson, E.A., Balan, K.V., Pantazis, P., Wyche, J.H., 2002. Role of p21 in apoptosis and senescence of human colon cancer cells treated with camptothecin. J. Biol. Chem., 277(19):17154-17160.

[97] Harris, M.H., Thompson, C.B., 2000. The role of the Bcl-2 family in the regulation of outer mitochondrial membrane permeability. Cell Death Differ., 7(12):1182-1191.

[98] Hegde, R., Srinivasula, S.M., Ahmad, M., Fernandes-Alnemri, T., Alnemri, E.S., 1998. Blk, a BH3-containing mouse protein that interacts with Bcl-2 and Bcl-xL, is a potent death agonist. J. Biol. Chem., 273(14):7783-7786.

[99] Hemann, M.T., Narita, M., 2007. Oncogenes and senescence: breaking down in the fast line. Genes Dev., 21(1):1-5.

[100] Herbig, U., Jobling, W.A., Chen, B.P., Chen, D.J., Sedrivy, J.M., 2004. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(Cip1), but not p16(INK4a). Mol. Cell, 14(4):501-513.

[101] Hermeking, H., Lengauer, C., Polyak, K., He, T., Zhang, L., Thiagalingam, S., 1997. 14-3-3 sigma is a p53-regulated inhibitor of G2/M progression. Mol. Cell, 1(1):3-11.

[102] Hershko, T., Ginsberg, D., 2004. Up-regulation of Bcl-2 homology 3 (BH3)-only proteins by E2F1 mediates apoptosis. J. Biol. Chem., 279(10):8627-8634.

[103] Hirota, T., Kunitoku, N., Sasayama, T., Marumoto, T., Zhang, D., Nitta, M., Hatakeyama, K., Saya, H., 2003. Aurora-A and an interacting activator, the LIM protein Ajuba, are required for mitotic commitment in human cells. Cell, 114(5):585-598.

[104] Hockenbery, D., Nunez, G., Milliman, C., Schreiber, R.D., Korsmeyer, S.J., 1990. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature, 348(6299):334-336.

[105] Hockenbery, D.M., Oltvai, Z.N., Yin, X.M., Milliman, C.L., Korsmeyer, S.J., 1993. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell, 75(2):241-251.

[106] Hofmann, K., Bucher, P., Kajava, A.V., 1998. A model of Cdc25 phosphatase catalytic domain and Cdk-interaction surface based on the presence of a rhodanese homology domain. J. Mol. Biol., 282(1):195-208.

[107] Holliday, R., Tarrant, G.M., 1972. Altered enzymes in ageing human fibroblasts. Nature, 238(5358):26-30.

[108] Holmberg, C., Helin, K., Sehested, M., Karlstrom, O., 1998. E2F-1-induced p53-independent apoptosis in transgenic mice. Oncogene, 17(2):143-155.

[109] Hsu, S.Y., Kaipia, A., McGee, E., Lomeli, M., Hsueh, A.J.W., 1997a. Bok is a pro-apoptotic Bcl-2 protein with restricted expression in reproductive tissues and heterodimerizes with selective anti-apoptotic Bcl-2 family members. Proc. Natl. Acad. Sci. (USA), 94(23):12401-12406.

[110] Hsu, Y.T., Wolter, K.G., Youle, R.J., 1997b. Cytosol-to-membrane redistribution of Bax and Bcl-X-L during apoptosis. Proc. Natl. Acad. Sci. (USA), 94(8):3668-3672.

[111] Hsu, S.Y., Lin, P., Hsueh, A.J.W., 1998. Bod (Bcl-2-related ovarian death gene) is an ovarian BH3 domain-containing proapoptotic Bcl-2 protein capable of dimerization with diverse antiapoptotic Bcl-2 members. Mol. Endocrinol., 12(9):1432-1440.

[112] Huang, D.C.S., Oreilly, L.A., Strasser, A., Cory, S., 1997. The anti-apoptosis function of Bcl-2 can be genetically separated from its inhibitory effect on cell cycle entry. EMBO J., 16(15):4628-4638.

[113] Hunt, K.K., Deng, J., Liu, T.J., Wilson-Heiner, M., Swisher, S.G., Clayman, G., Hung, M.C., 1997. Adenovirus-mediated overexpression of the transcription factor E2F-1 induces apoptosis in human breast and ovarian carcinoma cell lines and does not require p53. Cancer Res., 57:4722-4726.

[114] Hunter, T., Pines, J., 1994. Cyclins and cancer. 2: Cyclin D and CDK inhibitors come of age. Cell, 79(4):573-582.

[115] Imaizumi, K., Morihara, T., Mori, Y., Katayama, T., Tsuda, M., Furuyama, T., Wanaka, A., Takeda, M., Tohyama, M., 1999. The cell death-promoting gene DP5, which interacts with the BCL2 family, is induced during neuronal apoptosis following exposure to amyloid beta protein. J. Biol. Chem., 274(12):7975-7981.

[116] Innocente, S.A., Abrahamson, J.L., Cogswell, J.P., Lee, J.M., 1999. p53 regulates a G2 checkpoint through cyclin B1. Proc. Natl. Acad. Sci. (USA), 96(5):2147-2152.

[117] Inohara, N., Ding, L.Y., Chen, S., Nunez, G., 1997. Harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-X-L. EMBO J., 16(7):1686-1694.

[118] Inohara, N., Gourley, T.S., Carrio, R., Muniz, M., Merino, J., Garcia, I., Koseki, T., Hu, Y., Chen, S., Nunez, G., 1998a. Diva, a Bcl-2 homologue that binds directly to Apaf-1 and induces BH3-independent cell death. J. Biol. Chem., 273(49):32479-32486.

[119] Inohara, N., Ekhterae, D., Garcia, I., Carrio, R., Merino, J., Merry, A., Chen, S., Núñez, G., 1998b. Mtd, a novel Bcl-2 family member activates apoptosis in the absence of heterodimerization with Bcl-2 and Bcl-X-L. J. Biol. Chem., 273(15):8705-8710.

[120] Jacks, T., 1996. Tumor suppressor gene mutations in mice. Ann. Rev. Genet., 30(1):603-636.

[121] Jackson, J.P., Lindroth, A.M., Cao, X., Jacobsen, S.E., 2002. Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase. Nature, 416(6880):556-560.

[122] Jamil, S., Sobouti, R., Hojabrpour, P., Raj, M., Kast, J., Duronio, V., 2005. A proteolytic fragment of Mcl-1 exhibits nuclear localization and regulates cell growth via interaction with Cdk1. Biochem. J., 387(3):659-667.

[123] Johnstone, R.W., Ruefli, A.A., Lowe, S.W., 2002. Apoptosis. A link between cancer genetics and chemotherapy. Cell, 108(2):153-164.

[124] Jost, C.A., Marin, M.C., Kaelin, W.G., 1997. p73 is a human p53-related protein that can induce apoptosis. Nature, 389(6647):191-194.

[125] Kamer, I., Sarig, R., Zaltsman, Y., Niv, H., Oberkovitz, G., Regev, L., Haimovich, G., Lerenthal, Y., Marcellus, R., Gross, A., 2005. Proapoptotic Bid is an ATM effector in the DNA-damage response. Cell, 122(4):593-603.

[126] Kane, D.J., Sarafian, T.A., Anton, R., Hahn, H., Gralla, E.B., Valentine, J.S., Ord, T., Bredesen, D.E., 1993. Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Science, 262(5137):1274-1277.

[127] Kang, Y.K., Koo, D.B., Park, J.S., Choi, Y.H., Lee, K.K., Han, Y.M., 2001. Differential inheritance modes of DNA methylation between euchromatic and heterochromatic DNA sequences in ageing fetal bovine fibroblasts. FEBS Lett., 498(1):1-5.

[128] Kastan, M.B., Canman, C.E., Leonard, C.J., 1995. p53, cell cycle control and apoptosis: implications for cancer. Cancer Metast. Rev., 14(1):3-15.

[129] Kataoka, T., Holler, N., Micheau, O., Martinon, F., Tinel, A., Hofmann, K., Tschopp, J., 2001. Bcl-rambo, a novel Bcl-2 homologue that induces apoptosis via its unique C-terminal extension. J. Biol. Chem., 276(22):19548-19554.

[130] Kaufmann, S.H., 1989. Induction of endonucleolytic DNA cleavage in human acute myelogenous leukemia cells by etoposide, camptothecin, and other cytotoxic anticancer drugs: a cautionary note. Cancer Res., 49:5870-5878.

[131] Kaufmann, S.H., 1998. Cell death induced by topoisomerase-targeted drugs: more questions than answers. Biochim. Biophys. Acta, 1400:195-211.

[132] Kaufmann, W.K., Paules, R.S., 1996. DNA damage and cell cycle checkpoints. FASEB J., 10:238-247.

[133] Kaufmann, S.H., Earnshaw, W.C., 2000. Induction of apoptosis by cancer chemotherapy. Exp. Cell Res., 256(1):42-49.

[134] Ke, N., Godzik, A., Reed, J.C., 2001. Bcl-B, a novel Bcl-2 family member that differentially binds and regulates Bax and Bak. J. Biol. Chem., 276(16):12481-12484.

[135] Kelekar, A., Thompson, C.B., 1998. Bcl-2-family proteins: the role of the BH3 domain in apoptosis. Trends Cell Biol., 8(8):324-330.

[136] Kharbanda, S., Saxena, S., Yoshida, K., Pandey, P., Kaneki, M., Wang, Q., Cheng, K., Chen, Y.N., Campbell, A., Sudha, T., et al., 2000. Translocation of SAPK/JNK to mitochondria and interaction with Bcl-x(L) in response to DNA damage. J. Biol. Chem., 275(1):322-327.

[137] Kiefer, M.C., Brauer, M.J., Powers, V.C., Wu, J.J., Umansky, S.R., Tomei, L.D., Barr, P.J., 1995. Modulation of apoptosis by the widely distributed Bcl-2 homologue Bak. Nature, 374(6524):736-739.

[138] Kim, H., Rafiuddin-Shah, M., Tu, H.C., Jeffers, J.R., Zambetti, G.P., Hsieh, J.J.D., Cheng, E.H.Y., 2006. Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. Nat. Cell Biol., 8(12):1348-1358.

[139] King, R.W., Jackson, P.K., Kirschner, M.W., 1994. Mitosis in transition. Cell, 79(4):563-571.

[140] Kluck, R.M., Bossy-Wetzel, E., Green, D.R., Newmeyer, D.D., 1997. The release of cytochrome C from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science, 275(5303):1132-1136.

[141] Knowlton, K., Mancini, M., Creason, S., Morales, C., Hockenbery, D., Anderson, B.O., 1998. Bcl-2 slows in vitro breast cancer growth despite its antiapoptotic effect. J. Surg. Res., 76(1):22-26.

[142] Koff, A., Giordano, A., Desai, D., Yamashita, K., Harper, J.W., Elledge, S., Nishimoto, T., Morgan, D.O., Franza, B.R., Roberts, J.M., 1992. Formation and activation of a cyclinE-cdk2 complex during the G1 phase of the human cell cycle. Science, 257(5077):1689-1694.

[143] Kohn, K.W., 1996. Regulatory genes and drug sensitivity. J. Natl. Cancer Inst., 88(18):1255-1256.

[144] Kohn, K.W., Jackman, J., O'Connor, P.M., 1994. Cell cycle control and cancer chemotherapy. J. Cell. Biochem., 54(4):440-452.

[145] Korsmeyer, S.J., 1992. Bcl-2 initiates a new category of oncogenes: regulators of cell death. Blood, 80:879-886.

[146] Korsmeyer, S.J., Wei, M.C., Saito, M., Weiler, S., Oh, K.J., Schlesinger, P.H., 2000. Pro-apoptotic cascade activates Bid, which oligomerizes Bak or Bax into pores that result in the release of cytochrome c. Cell Death Differ., 7(12):1166-1173.

[147] Kozopas, K.M., Yang, T., Buchan, H.L., Zhou, P., Craig, R.W., 1993. Mcl1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to Bcl-2. Proc. Natl. Acad. Sci. (USA), 90(8):3516-3520.

[148] Krajewski, S., Tanaka, S., Takayama, S., Schibler, M.J., Fenton, W., Reed, J.C., 1993. Investigation of the subcellular distribution of the bcl-2 oncoprotein: residence in the nuclear envelope, endoplasmic reticulum, and outer mitochondrial membranes. Cancer Res., 53:4701-4714.

[149] Krajewski, S., Krajewska, M., Ellerby, L.M., Welsh, K., Xie, Z.H., Deveraux, Q.L., Salvesen, G.S., Bredesen, D.E., Rosenthal, R.E., Fiskum, G., Reed, J.C., 1999. Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia. Proc. Natl. Acad. Sci. (USA), 96(10):5752-5757.

[150] Kudla, G., Montessuit, S., Eskes, R., Berrier, C., Martinou, J.C., Ghazi, A., Antonsson, B., 2000. The destabilization of lipid membranes induced by the C-terminal fragment of caspase 8-cleaved bid is inhibited by the N-terminal fragment. J. Biol. Chem., 275(30):22713-22718.

[151] Kung, A.L., Zetterberg, A., Sherwood, S.W., Schimke, R.T., 1990. Cytotoxic effects of cell cycle phase specific agents: result of cell cycle perturbation. Cancer Res., 50:7307-7317.

[152] Kuwana, T., Mackey, M.R., Perkins, G., Ellisman, M., Latterich, M., Schneiter, R., Green, D., Newmeyer, D., 2002. Bid, bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell, 111(3):331-342.

[153] Kuwana, T., Bouchier-Hayes, L., Chipuk, J.E., Bonzon, C., Sullivan, B.A., Green, D.R., Newmeyer, D.D., 2005. BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol. Cell, 17(4):525-535.

[154] Labib, K., Craven, R.A., Crawford, K., Nurse, P., 1995. Dominant mutants identify new roles for p34cdc2 in mitosis. EMBO J., 14:2155-2165.

[155] Lammer, C., Wagerer, S., Saffrich, R., Mertens, D., Ansorge, W., Hoffmann, I., 1998. The cdc25B phosphatase is essential for the G2/M phase transition in human cells. J. Cell Sci., 111:2445-2453.

[156] Lee, S., Schmitt, C.A., 2003. Chemotherapy response and resistance. Curr. Opin. Genet. Dev., 13(1):90-96.

[157] Letai, A., Bassik, M., Walensky, L., Sorcinelli, M., Weiler, S., Korsmeyer, S., 2002. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell, 2(3):183-192.

[158] Leu, J.I.J., Dumont, P., Hafey, M., Murphy, M.E., George, D.L., 2004. Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nat. Cell Biol., 6(5):443-450.

[159] Levine, A.J., 1997. p53, the cellular gatekeeper for growth and division. Cell, 88(3):323-331.

[160] Li, L.Y., Luo, X., Wang, X., 2001. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature, 412(6842):95-99.

[161] Lin, E.Y., Orlofsky, A., Berger, M.S., Prystowsky, M.B., 1993. Characterization of A1, a novel hemopoietic-specific early-response gene with sequence similarity to bcl-2. J. Immunol., 151:1979-1988.

[162] Linette, G.P., Li, Y., Roth, K., Korsmeyer, S.J., 1996. Cross talk between cell death and cell cycle progression: BCL-2 regulates NFAT-mediated activation. Proc. Natl. Acad. Sci. (USA), 93(18):9545-9552.

[163] Ling, Y.H., Tornos, C., Perez-Soler, R., 1998. Phosphorylation of Bcl-2 is a marker of M phase events and not a determinant of apoptosis. J. Biol. Chem., 273(30):18984-18991.

[164] Linke, S.P., Clarkin, K.C., Wahl, G.M., 1997. p53 mediates permanent arrest over multiple cell cycles in response to gamma-irradiation. Cancer Res., 57:1171-1179.

[165] Liu, F., Stanton, J.J., Wu, Z., 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.

[166] Liu, Q., Guntuku, S., Cui, X.S., Matsuoka, S., Cortez, D., Tamai, K., Luo, G., Carattini-Rivera, S., DeMayo, F., Bradley, A., Donehower, L.A., Elledge, S.J., 2000. Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes Dev., 14(12):1448-1459.

[167] Liu, Z., Lu, H., Jiang, Z.H., Pastuszyn, A., Hu, C.A., 2005. Apolipoprotein L6, a novel proapoptotic Bcl-2 homology 3-only protein, induces mitochondria-mediated apoptosis in cancer cells. Mol. Cancer Res., 3:21-31.

[168] Lopatina, N., Haskell, J.F., Andrews, L.G., Poole, J.C., Saldanha, S., Tollefsbol, T., 2002. Differential maintenance and de novo methylating activity by three DNA methyltransferases in aging and immortalized fibroblasts. J. Cell. Biochem., 84(2):324-334.

[169] Lowe, S.W., Ruley, H.E., Jacks, T., Housman, D.E., 1993. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell, 74(6):957-967.

[170] Lowe, S.W., Bodis, S., McClatchey, A., Remington, L., Ruley, H.E., Fisher, D.E., Housman, D.E., Jacks, T., 1994. p53 status and the efficacy of cancer therapy in vivo. Science, 266(5186):807-810.

[171] Lukas, J., Lukas, C., Bartek, J., 2004. Mammalian cell cycle checkpoints: signalling pathways and their organization in space and time. DNA Repair (Amst.), 3(8-9):997-1007.

[172] Machwe, A., Orren, D.K., Bohr, V.A., 2000. Accelerated methylation of ribosomal RNA genes during the cellular senescence of Werner syndrome fibroblasts. FASEB J., 14(12):1715-1724.

[173] Mallette, F.A., Gaumont-Leclerc, M.F., Ferbeyre, G., 2007. The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence. Genes Dev., 21(1):43-48.

[174] Mancini, M., Nicholson, D.W., Roy, S., Thornberry, N.A., Peterson, E.P., Casciola-Rosen, L.A., Rosen, A., 1998. The caspase-3 precursor has a cytosolic and mitochondrial distribution: implications for apoptotic signaling. J. Cell Biol., 140(6):1485-1495.

[175] Marumoto, T., Hirota, T., Morisaki, T., Kunitoku, N., Zhang, D., Ichikawa, Y., Sasayama, T., Kuninaka, S., Mimori, T., Tamaki, N., Kimura, M., Okano, Y., Saya, H., 2002. Roles of aurora-A kinase in mitotic entry and G2 checkpoint in mammalian cells. Genes Cells, 7(11):1173-1182.

[176] Marzo, I., Brenner, C., Zamzami, N., Jurgensmeier, J.M., Susin, S.A., Vieira, H.L., Prevost, M.C., Xie, Z., Matsuyama, S., Reed, J.C., Kroemer, G., 1998. Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. Science, 281(5385):2027-2031.

[177] Matsuoka, S., Huang, M., Elledge, S.J., 1998. Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science, 282(5395):1893-1897.

[178] Matsushima, M., Fujiwara, T., Takahashi, E., Minaguchi, T., Eguchi, Y., Tsujimoto, Y., Suzumori, K., Nakamura, Y., 1998. Isolation, mapping, and functional analysis of a novel human cDNA (BNIP3L) encoding a protein homologous to human NIP3. Genes. Chromos. Cancer, 21(3):230-235.

[179] Maundrell, K., Antonsson, B., Magnenat, E., Camps, M., Muda, M., Chabert, C., Gillieron, C., Boschert, U., Vial-Knecht, E., Martinou, J.C., Arkinstall, S., 1997. Bcl-2 undergoes phosphorylation by C-Jun N-terminal kinase stress-activated protein kinases in the presence of the constitutively active GTP-binding protein Rac1. J. Biol. Chem., 272(40):25238-25242.

[180] Mazel, S., Burtrum, D., Petrie, H.T., 1996. Regulation of cell division cycle progression by bcl-2 expression: a potential mechanism for inhibition of programmed cell death. J. Exp. Med., 183(5):2219-2226.

[181] McDonnell, T.J., Marin, M.C., Hsu, B., Brisbay, S.M., McConnell, K., Tu, S.M., Campbell, M.L., Rodriguez-Villanueva, J., 1993. The Bcl-2 oncogene: apoptosis and neoplasia. Radiation Res., 136(3):307-312.

[182] McDonnell, J.M., Fushman, D., Milliman, C.L., Korsmeyer, S.J., Cowburn, D., 1999. Solution structure of the proapoptotic molecule BID: a structural basis for apoptotic agonists and antagonists. Cell, 96(5):625-634.

[183] McGowan, C.H., Russell, P., 1995. Cell cycle regulation of human Wee1. EMBO J., 14:2166-2175.

[184] Melino, G., Bernassola, F., Ranalli, M., Yee, K., Zong, W.X., Corazzari, M., Knight, R.A., Green, D.R., Thompson, C., Vousden, K.H., 2004. p73 induces apoptosis via PUMA transactivation and Bax mitochondrial translocation. J. Biol. Chem., 279(9):8076-8083.

[185] Mercurio, F., Manning, A.M., 1999. NF-κB as a primary regulator of the stress response. Oncogene, 18(45):6163-6171.

[186] Mihara, M., Erster, S., Zaika, A., Petrenko, O., Chittenden, T., Pancoska, P., Moll, U.M., 2003. p53 has a direct apoptogenic role at the mitochondria. Mol. Cell, 11(3):577-590.

[187] Minn, A.J., Velez, P., Schendel, S.L., Liang, H., Muchmore, S.W., Fesik, S.W., Fill, M., Thompson, C.B., 1997. Bcl-xL forms an ion channel in synthetic lipid membranes. Nature, 385(6614):353-357.

[188] Miyashita, T., Reed, J.C., 1995. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell, 80(2):293-299.

[189] Miyashita, T., Krajewski, S., Krajewska, M., Wang, H.G., Lin, H.K., Liebermann, D.A., Hoffman, B., Reed, J.C., 1994. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene, 9:1799-1805.

[190] Muchmore, S.W., Sattler, M., Liang, H., Meadows, R.P., Harlan, J.E., Yoon, H.S., Nettesheim, D., Chang, B.S., Thompson, C.B., Wong, S.L., Ng, S.C., Fesik, S.W., 1996. X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature, 381(6580):335-341.

[191] Mueller, P.R., Coleman, T.R., Kumagai, A., Dunphy, W.G., 1995. Myt1: a membrane-associated inhibitory kinase that phosphorylates Cdc2 on both threonine-14 and tyrosine-15. Science, 270(5233):86-90.

[192] Muller, H., Bracken, A.P., Vernell, R., Moroni, M.C., Christians, F., Grassilli, E., Prosperini, E., Vigo, E., Oliner, J.D., Helin, K., 2001. E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis. Genes Dev., 15(3):267-285.

[193] Nakano, K., Vousden, K.H., 2001. Puma, a novel proapoptotic gene, is induced by p53. Mol. Cell, 7(3):683-694.

[194] Neumeister, P., Albanese, C., Balent, B., Greally, J., Pestell, R.G., 2002. Senescence and epigenetic dysregulation in cancer. Int. J. Biochem. Cell Biol., 34(11):1475-1490.

[195] Nguyen, M., Branton, P.E., Walton, P.A., Oltvai, Z.N., Korsmeyer, S.J., Shore, G.C., 1994. Role of membrane anchor domain of Bcl-2 in suppression of apoptosis caused by E1B-defective adenovirus. J. Biol. Chem., 269:16521-16524.

[196] Nicotera, P., Leist, M., Ferrando-May, E., 1999. Apoptosis and necrosis: different execution of the same death. Biochem. Soc. Symp., 66:69-73.

[197] Nigg, E.A., 2001. Mitotic kinases as regulators of cell division and its checkpoints. Nat. Rev. Mol. Cell Biol., 2(1):21-32.

[198] Nozell, S., Wu, Y., McNaughton, K., Liu, G., Willis, A., Paik, J.C., Chen, X., 2003. Characterization of p73 functional domains necessary for transactivation and growth suppression. Oncogene, 22(28):4333-4347.

[199] O'Connell, M.J., Raleigh, J.M., Verkade, H.M., Nurse, P., 1997. Chk 1 is a wee 1 kinase in the G2 DNA damage checkpoint inhibiting cdc2 by Y15 phosphorylation. EMBO J., 16(3):545-554.

[200] O'Connor, P.M., 1997. Mammalian G1 and G2 phase checkpoints. Cancer Surv., 29:151-182.

[201] O'Connor, P.M., Jackman, J., Bae, I., Myers, T.G., Fan, S., Mutoh, M., Scudiero, D.A., Monks, A., Sausville, E.A., Weinstein, J.N., et al., 1997. Characterization of the p53 tumor suppressor pathway in cell lines of the National Cancer Institute drug screen and correlations with the growth-inhibitory potency of 123 anticancer agents. Cancer Res., 57:4285-4300.

[202] O'Connor, L., Strasser, A., O'Reilly, L.A., Hausmann, G., Adams, J.M., Cory, S., Huang, D.C., 1998. Bim: a novel member of the Bcl-2 family that promotes apoptosis. EMBO J., 17(2):384-395.

[203] Oda, E., Ohki, R., Murasawa, H., Nemoto, J., Shibue, T., Yamashita, Y., Tokino, T., Taniguchi, T., Tanaka, N., 2000. Noxa, a BH3-only member of the bcl-2 family and candidate mediator of p53-induced apoptosis. Science, 288(5468):1053-1058.

[204] Ogilvy, S., Metcalf, D., Print, C.G., Bath, M.L., Harris, A.W., Adams, J.M., 1999. Constitutive Bcl-2 expression throughout the hematopoietic compartment affects multiple lineages and enhances progenitor cell survival. Proc. Natl. Acad. Sci. (USA), 96(26):14943-14948.

[205] Oltvai, Z.N., Milliman, C.L., Korsmeyer, S.J., 1993. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell, 74(4):609-619.

[206] O'Reilly, L.A., Huang, D.C.S., Strasser, A., 1996. The death inhibitor Bcl-2 and its homologues influence control of cell cycle. EMBO J., 15:6979-6990.

[207] O'Reilly, L.A., Harris, A.W., Strasser, A., 1997a. Bcl-2 transgene expression promotes survival and reduces proliferation of CD3-CD4-CD8-T cell progenitors. Int. Immunol., 9(9):1291-1301.

[208] O'Reilly, L.A., Harris, A.W., Tarlinton, D.M., Corcoran, L.M., Strasser, A., 1997b. Expression of a Bcl-2 transgene reduces proliferation and slows turnover of developing B lymphocytes in vivo. J. Immunol., 159:2301-2311.

[209] Parrish, J., Li, L., Klotz, K., Ledwich, D., Wang, X., Xue, D., 2001. Mitochondrial endonuclease G is important for apoptosis in C. elegans. Nature, 412(6842):90-94.

[210] Passalaris, T.M., Benanti, J.A., Gewin, L., Kiyono, T., Galloway, D.A., 1999. The G(2) checkpoint is maintained by redundant pathways. Mol. Cell Biol., 19:5872-5881.

[211] Pavlov, E.V., Priault, M., Pietkiewicz, D., Cheng, E.H.Y., Antonsson, B., Manon, S., Korsmeyer, S.J., Mannella, C.A., Kinnally, K.W., 2001. A novel, high conductance channel of mitochondria linked to apoptosis in mammalian cells and Bax expression in yeast. J. Cell Biol., 155(5):725-732.

[212] Pediconi, N., Ianari, A., Costanzo, A., Belloni, L., Gallo, R., Cimino, L., Porcellini, A., Screpanti, I., Balsano, C., Alesse, E., Gulino, A., Massimo Levrero, M., 2003. Differential regulation of E2F1 apoptotic target genes in response to DNA damage. Nat. Cell Biol., 5(6):552-558.

[213] Peng, C.Y., Graves, P.R., Thoma, R.S., Wu, Z., Shaw, A.S., Piwnica-Worms, H., 1997. Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. Science, 277(5331):1501-1505.

[214] Perfettini, J.L., Kroemer, R.T., Kroemer, G., 2004. Fatal liaisons of p53 with bax and Bak. Nat. Cell Biol., 6(5):386-387.

[215] Phillips, A.C., Bates, S., Ryan, K.M., Helin, K., Vousden, K.H., 1997. Induction of DNA synthesis and apoptosis are separable functions of E2F-1. Genes Dev, 11:1853-1863.

[216] Piret, B., Schoonbroodt, S., Piette, J., 1999. The ATM protein is required for sustained activation of NF-kappa B following DNA damage. Oncogene, 18(13):2261-2271.

[217] Polster, B.M., Kinnally, K.W., Fiskum, G., 2001. BH3 death domain peptide induces cell type-selective mitochondrial outer membrane permeability. J. Biol. Chem., 276:37887-37894.

[218] Poruchynsky, M.S., Wang, E.E., Rudin, C.M., Blagosklonny, M.V., Fojo, T., 1998. Bcl-X(L) is phosphorylated in malignant cells following microtubule disruption. Cancer Res., 58:3331-3338.

[219] Puthalakath, H., Huang, D.C.S., O'Reilly, L.A., King, S.M., Strasser, A., 1999. The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol. Cell, 3(3):287-296.

[220] Puthalakath, H., Villunger, A., O'Reilly, L.A., Beaumont, J.G., Coultas, L., Cheney, R.E., Huang, D.C., Strasser, A., 2001. Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis. Science, 293(5536):1829-1832.

[221] Qin, Z.H., Wang, Y., Kikly, K.K., Sapp, E., Kegel, K.B., Aronin, N., DiFiglia, M., 2001. Pro-caspase-8 is predominantly localized in mitochondria and released into cytoplasm upon apoptotic stimulation. J. Biol. Chem., 276(11):8079-8086.

[222] Reed, J.C., 1997. Double identity for proteins of the Bcl-2 family. Nature, 387(6635):773-776.

[223] Reed, J.C., 1998. Bcl-2 family proteins. Oncogene, 17(25):3225-3236.

[224] Reed, J.C., 2006. Drug insight: cancer therapy strategies based on restoration of endogenous cell death mechanisms. Nat. Clin. Pract. Oncol., 3(7):388-398.

[225] Riabowol, K., Draetta, G., Brizuela, L., Vandre, D., Beach, D., 1989. The cdc2 kinase is a nuclear protein that is essential for mitosis in mammalian cells. Cell, 57(3):393-401.

[226] Robles, S.J., Adami, G.R., 1998. Agents that cause DNA double strand breaks lead to p16INK4a enrichment and the premature senescence of normal fibroblasts. Oncogene, 16(9):1113-1123.

[227] Ruvolo, P.P., Deng, X.M., Carr, B.H., May, W.S., 1998. A functional role for mitochondrial protein kinase C-alpha in Bcl2 phosphorylation and suppression of apoptosis. J. Biol. Chem., 273(39):25436-25442.

[228] Ryan, K.M., Ernst, M.K., Rice, N.R., Vousden, K.H., 2000. Role of NFκB in p53-mediated programmed cell death. Nature, 404(6780):892-896.

[229] Saito, M., Korsmeyer, S.J., Schlesinger, P.H., 2000. Bax-dependent transport of cytochrome c reconstituted in pure liposomes. Nat. Cell. Biol., 2(8):553-555.

[230] Sanchez, Y., Wong, C., Thoma, R.S., Richman, R., Wu, Z., Piwnica-Worms, H., Elledge, S.J., 1997. Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25. Science, 277(5331):1497-1501.

[231] Sattler, M., Liang, H., Nettesheim, D., Meadows, R.P., Harlan, J.E., Eberstadt, M., Yoon, H.S., Shuker, S.B., Chang, B.S., Minn, A.J., et al., 1997. Structure of Bcl-x(L)-Bak peptide complex: recognition between regulators of apoptosis. Science, 275(5302):983-986.

[232] Sax, J.K., Fei, P., Murphy, M.E., Bernhard, E., Korsmeyer, S.J., El-Deiry, W.S., 2002. BID regulation by p53 contributes to chemosensitivity. Nat. Cell Biol., 4(11):842-849.

[233] Scatena, C.D., Stewart, Z.A., Mays, D., Tang, L.J., Keefer, C.J., Leach, S.D., Pietenpol, J.A., 1998. Mitotic phosphorylation of Bcl-2 during normal cell cycle progression and Taxol-induced growth arrest. J. Biol. Chem., 273(46):30777-30784.

[234] Schendel, S.L., Montal, M., Reed, J.C., 1998. Bcl-2 family proteins as ion-channels. Cell Death Differ., 5(5):372-380.

[235] Schlesinger, P.H., Gross, A., Yin, X.M., Yamamoto, K., Saito, M., Waksman, G., Korsmeyer, S.J., 1997. Comparison of the ion channel characteristics of proapoptotic Bax and antiapoptotic Bcl-2. Proc. Natl. Acad. Sci. (USA), 94(21):11357-11362.

[236] Schmitt, C.A., 2007. Cellular senescence and cancer treatment. Biochim. Biophys. Acta, 1775:5-20.

[237] Schmitt, C.A., Fridman, J.S., Yang, M., Lee, S., Baranov, E., Hoffman, R.M., Lowe, S.W., 2002. A senescence program controlled by p53 and p16(INK4a) contributes to the outcome of cancer therapy. Cell, 109(3):335-346.

[238] Schmitt, E., Paquet, C., Beauchemin, M., Bertrand, R., 2004. Bcl-xES, a BH4- and BH2-containing antiapoptotic protein, delays Bax oligomer formation and binds Apaf-1, blocking procaspase 9 activation. Oncogene, 23(22):3915-3931.

[239] Schmitt, E., Boutros, R., Froment, C., Monsarrat, B., Ducommun, B., Dozier, C., 2006. CHK1 phosphorylates CDC25B during the cell cycle in the absence of DNA damage. J. Cell Sci., 119(20):4269-4275.

[240] Schmitt, E., Beauchemin, M., Bertrand, R., 2007. Nuclear co-localization and interaction between bcl-xL and cdk1(cdc2) during G2/M cell cycle checkpoint. Oncogene, in press.

[241] Sedlak, T.W., Oltvai, Z.N., Yang, E., Wang, K., Boise, L.H., Thompson, C.B., Korsmeyer, S.J., 1995. Multiple Bcl-2 family members demonstrate selective dimerizations with Bax. Proc. Natl. Acad. Sci. (USA), 92(17):7834-7838.

[242] Sherr, C.J., Roberts, J.M., 1995. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes. Dev., 9:1149-1163.

[243] Shibue, T., Takeda, K., Oda, E., Tanaka, H., Murasawa, H., Takaoka, A., Morishita, Y., Akira, S., Taniguchi, T., Tanaka, N., 2003. Integral role of Noxa in p53-mediated apoptotic response. Genes Dev., 17(18):2233-2238.

[244] Shiloh, Y., 2001. ATM and ATR: networking cellular responses to DNA damage. Curr. Opin. Genet. Dev., 11(1):71-77.

[245] Shiloh, Y., 2006. The ATM-mediated DNA-damage response: taking shape. Trends Biochem. Sci., 31(7):402-410.

[246] Shimizu, T., Pommier, Y., 1997. Camptothecin-induced apoptosis in p53-null human leukemia Hl60 cells and their isolated nuclei; Effects of the protease inhibitors z-VAD-fmk and dichloroisocoumarin suggest an involvement of both caspases and serine proteases. Leukemia, 11(8):1238-1244.

[247] Shimizu, S., Tsujimoto, Y., 2000. Proapoptotic BH3-only Bcl-2 family members induce cytochrome c release, but not mitochondrial membrane potential loss, and do not directly modulate voltage-dependent anion channel activity. Proc. Natl. Acad. Sci. (USA), 97(2):577-582.

[248] Shimizu, S., Eguchi, Y., Kamiike, W., Funahashi, Y., Mignon, A., Lacronique, V., Matsuda, H., Tsujimoto, Y., 1998. Bcl-2 prevents apoptotic mitochondrial dysfunction by regulating proton flux. Proc. Natl. Acad. Sci. (USA), 95(4):1455-1459.

[249] Shimizu, S., Narita, M., Tsujimoto, Y., 1999. Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature, 399(6735):483-487.

[250] Shimizu, S., Konishi, A., Kodama, T., Tsujimoto, Y., 2000. BH4 domain of antiapoptotic bcl-2 family members closes voltage-dependent anion channel and inhibits apoptotic mitochondrial changes and cell death. Proc. Natl. Acad. Sci. (USA), 97(7):3100-3105.

[251] Slichenmyer, W.J., Nelson, W.G., Slebos, R.J., Kastan, M.B., 1993. Loss of a p53-associated G1 checkpoint does not decrease cell survival following DNA damage. Cancer Res., 53:4164-4168.

[252] Smits, V.A.J., Klompmaker, R., Arnaud, L., Rijksen, G., Nigg, E.A., Medema, R.H., 2000. Polo-like kinase-1 is a target of the DNA damage checkpoint. Nat. Cell Biol., 2(9):672-676.

[253] Solary, E., Bertrand, R., Jenkins, J., Pommier, Y., 1992. Radiolabeling of DNA can induce its fragmentation in HL-60 promyelocytic leukemic cells. Exp. Cell Res., 203(2):495-498.

[254] Song, Q.Z., Kuang, Y.P., Dixit, V.M., Vincenz, C., 1999. Boo, a novel negative regulator of cell death, interacts with Apaf-1. EMBO J., 18(1):167-178.

[255] Srivastava, R.K., Srivastava, A.R., Korsmeyer, S.J., Nesterova, M., Chochung, Y.S., Longo, D.L., 1998. Involvement of microtubules in the regulation of Bcl2 phosphorylation and apoptosis through cyclic AMP-dependent protein kinase. Mol. Cell Biol., 18:3509-3517.

[256] Srivastava, R.K., Mi, Q.S., Hardwick, J.M., Longo, D.L., 1999. Deletion of the loop region of Bcl-2 completely blocks paclitaxel-induced apoptosis. Proc. Natl. Acad. Sci. (USA), 96(7):3775-3780.

[257] Stanelle, J., Stiewe, T., Theseling, C.C., Peter, M., Pützer, B.M., 2002. Gene expression changes in response to E2F1 activation. Nucleic. Acids Res., 30(8):1859-1867.

[258] Stehlik, C., Demartin, R., Kumabashiri, I., Schmid, J.A., Binder, B.R., Lipp, J., 1998. Nuclear factor (NF)-kappaB-regulated X-chromosome-linked Iap gene expression protects endothelial cells from tumor necrosis factor alpha-induced apoptosis. J. Exp. Med., 188(1):211-216.

[259] Stiewe, T., Pützer, B.M., 2000. Role of the p53-homologue p73 in E2F1-induced apoptosis. Nat. Genet., 26(4):464-469.

[260] Stroka, D.M., Badrichani, A.Z., Bach, F.H., Ferran, C., 1999. Overexpression of A1, an NF-kappaB-inducible anti-apoptotic Bcl gene, inhibits endothelial cell activation. Blood, 93:3803-3810.

[261] Strunnikova, M., Schagdarsurengin, U., Kehlen, A., Garbe, J.C., Stampfer, M.R., Dammann, R., 2005. Chromatin inactivation precedes de novo DNA methylation during the progressive epigenetic silencing of the RASSF1A promoter. Mol. Cell. Biol., 25(10):3923-3933.

[262] Sugiyama, T., Shimizu, S., Matsuoka, Y., Yoneda, Y., Tsujimoto, Y., 2002. Activation of mitochondrial voltage-dependent anion channel by apro-apoptotic BH3-only protein Bim. Oncogene, 21(32):4944-4956.

[263] Sun, L.Q., Arceci, R.J., 2005. Altered epigenetic patterning leading to replicative senescence and reduced longevity. A role of a novel SNF2 factor, PASG. Cell Cycle, 4:3-5.

[264] Susin, S.A., Zamzami, N., Castedo, M., Hirsch, T., Marchetti, P., Macho, A., Daugas, E., Geuskens, M., Kroemer, G., 1996. Bcl-2 inhibits the mitochondrial release of an apoptogenic protease. J. Exp. Med., 184(4):1331-1341.

[265] Susin, S.A., Lorenzo, H.K., Zamzami, N., Isabel Marzo, I., Snow, B.E., Brothers, G.M., Mangion, J., Jacotot, E., Costantini, P., Loeffler, M., et al., 1999a. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature, 397(6718):441-446.

[266] Susin, S.A., Lorenzo, H.K., Zamzami, N., Marzo, I., Brenner, C., Larochette, N., Prevost, M.C., Alzari, P.M., Kroemer, G., 1999b. Mitochondrial release of caspase-2 and -9 during the apoptotic process. J. Exp. Med., 189(2):381-393.

[267] Suzuki, K., Mori, I., Nakayama, Y., Miyakoda, M., Komada, S., Watanabe, M., 2001a. Radiation-induced senescence-like growth arrest requires TP53 function but not telomere shortening. Radiat. Res., 155(1):248-253.

[268] Suzuki, Y., Imai, Y., Nakayama, H., Takahashi, K., Takio, K., Takahashi, R., 2001b. A serine protease, Htra2, is released from the mitochondria and interacts with Xiap, inducing cell death. Mol. Cell, 8(3):613-621.

[269] Takahashi, A., Ohtani, N., Yamakoshi, K., Iida, S., Tahara, H., Nakayama, K., Nakayama, K.I., Ide, T., Saya, H., Hara, E., 2006. Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nat. Cell Biol., 8(11):1291-1297.

[270] Tamaru, H., Selker, E.U., 2001. A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature, 414(6861):277-283.

[271] Tamaru, H., Zhang, X., McMillen, D., Singh, P.B., Nakayama, J., Grewal, S.I., Allis, C.D., Cheng, X., Selker, E.U., 2003. Trimethylated lysine 9 of histone H3 is a mark for DNA methylation in Neurospora crassa. Nat. Genet., 34(1):75-79.

[272] Tamatani, M., Che, Y.H., Matsuzaki, H., Ogawa, S., Okado, H., Miyake, S., Mizuno, T., Tohyama, M., 1999. Tumor necrosis factor induces Bcl-2 and Bcl-x expression through NF kappa B activation in primary hippocampal neurons. J. Biol. Chem., 274(13):8531-8538.

[273] Tan, K.O., Tan, K.M.L., Chan, S.L., Yee, K.S.Y., Bevort, M., Ang, K.C., Yu, V.C., 2001. MAP-1, a novel proapototic protein containing a BH3-like motif that associates with Bax through its Bcl-2 homology domains. J. Biol. Chem., 276(4):2802-2807.

[274] Tanaka, N., Ishihara, M., Lamphier, M.S., Nozawa, H., Matsuyama, T., Mak, T.W., Aizawa, S., Tokino, T., Oren, M., Taniguchi, T., 1996. Cooperation of the tumour suppressors Irf-1 and p53 in response to DNA damage. Nature, 382(6594):816-818.

[275] Thomas, A., Elrouby, S., Reed, J.C., Krajewski, S., Silber, R., Potmseil, M., Newcomb, E.W., 1996. Drug-induced apoptosis in B-cell chronic lymphocytic leukemia: relationship between p53 gene mutation and Bcl-2/Bax proteins in drug resistance. Oncogene, 12:1055-1062.

[276] Tollefsbol, T.O., Andrews, L.G., 1993. Mechanisms for methylation-mediated gene silencing and aging. Med. Hypotheses, 41(1):83-92.

[277] Tsujimoto, Y., Finger, L.R., Yunis, J., Nowell, P.C., Croce, C.M., 1984. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14:18) chromosome translocation. Science, 226(4678):1097-1099.

[278] Vail, M.E., Chaisson, M.L., Thompson, J., Fausto, N., 2002. Bcl-2 expression delays hepatocyte cell cycle progression during liver regeneration. Oncogene, 21(10):1548-1555.

[279] Vairo, G., Innes, K.M., Adams, J.M., 1996. Bcl-2 has a cell cycle inhibitory function separable from its enhancement of cell survival. Oncogene, 13:1511-1519.

[280] van Vugt, M.A., Smits, V.A., Klompmaker, R., 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(45):41656-41660.

[281] Vander Heiden, M.G., Thompson, C.B., 1999. Bcl-2 proteins: regulators of apoptosis or of mitochondrial homeostasis? Nat. Cell Biol., 1(8):E209-E216.

[282] Vander Heiden, M.G., Chandel, N.S., Williamson, E.K., Schumacker, P.T., Thompson, C.B., 1997. Bcl-X(L) regulates the membrane potential and volume homeostasis of mitochondria. Cell, 91(5):627-637.

[283] Vaux, D.L., Cory, S., Adams, J.M., 1988. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature, 335(6189):440-442.

[284] Verhagen, A.M., Ekert, P.G., Pakusch, M., Silke, J., Connolly, L.M., Reid, G.E., Moritz, R.L., Simpson, R.J., Vaux, D.L., 2000. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell, 102(1):43-53.

[285] Villunger, A., Michalak, E.M., Coultas, L., Müllauer, F., Böck, G., Ausserlechner, M.J., Adams, J.M., Strasser, A., 2003. p53- and drug-induced apoptotic responses mediated by BH3-only proteins Puma and Noxa. Science, 302(5647):1036-1038.

[286] Waldman, T., Lengauer, C., Kinzler, K.W., Vogelstein, B., 1996. Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. Nature, 381(6584):713-716.

[287] Wang, K., Yin, X.M., Chao, D.T., Milliman, C.L., Korsmeyer, S.J., 1996. BID: a novel BH3 domain-only death agonist. Genes. Dev., 10:2859-2869.

[288] Wang, C.Y., Mayo, M.W., Korneluk, R.G., Goeddel, D.V., Baldwin, A.S., 1998. NF-kappa-B antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science, 281(5383):1680-1683.

[289] Wang, X.W., Zhan, Q.M., Coursen, J.D., Khan, M.A., Kontny, H.U., Yu, L., M. Hollander, M.C., O'Connor, P.M., Fornace, A.J.Jr, Harris, C.C., 1999a. GADD45 induction of a G(2)/M cell cycle checkpoint. Proc. Natl. Acad. Sci. (USA), 96(7):3706-3711.

[290] Wang, C.Y., Guttridge, D.C., Mayo, M.W., Baldwin, A.S.Jr, 1999b. NF-kappaB induces expression of the Bcl-2 homologue A1/Bfl-1 to preferentially suppress chemotherapy-induced apoptosis. Mol. Cell Biol., 19:5923-5929.

[291] Willis, S.N., Chen, L., Dewson, G., Wei, A., Naik, E., Fletcher, J.I., Adams, J.M., Huang, D.C.S., 2005. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev., 19(11):1294-1305.

[292] Willis, S.N., Fletcher, J.I., Kaufmann, T., van Delft, M.F., Chen, L., Czabotar, P.E., Ierino, H., Lee, E.H., Fairlie, W.D., Bouillet, P., et al., 2007. Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science, 315(5813):856-859.

[293] Xie, S., Wu, H., Wang, Q., Cogswell, J.P., Husain, I., Conn, C., Stambrook, P., Jhanwar-Uniyal, M., Dai, W., 2001. Plk3 functionally links DNA damage to cell cycle arrest and apoptosis at least in part via the p53 pathway. J. Biol. Chem., 276(46):43305-43312.

[294] Yamamoto, K., Ichijo, H., Korsmeyer, S.J., 1999. Bcl-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M. Mol. Cell Biol., 19:8469-8478.

[295] Yang, E., Zha, J., Jockel, J., Boise, L.H., Thompson, C.B., Korsmeyer, S.J., 1995. Bad, a heterodimeric partner for Bcl-xL and Bcl-2, displaces Bax and promotes cell death. Cell, 80(2):285-291.

[296] Yang, J., Liu, X., Bhalla, K., Kim, C.N., Ibrado, A.M., Cai, J., Peng, T.I., Jones, D.P., Wang. X., 1997. Prevention of apoptosis by Bcl-2: release of cytochrome C from mitochondria blocked. Science, 275(5303):1129-1132.

[297] Yang, A.N., Kaghad, M., Wang, Y.M., Gillett, E., Fleming, M.D., Dotsch, V., Andrews, N.C., Caput, D., McKeon, F., 1998. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol. Cell, 2(3):305-316.

[298] Yasuda, M., Han, J.W., Dionne, C.A., Boyd, J.M., Chinnadurai, G., 1999. BNIP3 alpha: a human homolog of mitochondrial proapoptotic protein BNIP3. Cancer Res., 59:533-537.

[299] Yin, X.M., Oltvai, Z.N., Korsmeyer, S.J., 1994. BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature, 369(6478):321-323.

[300] Yu, J., Zhang, L., Hwang, P.M., Kinzler, K.W., Vogelstein, B., 2001. Puma induces the rapid apoptosis of colorectal cancer cells. Mol. Cell, 7(3):673-682.

[301] Yuan, Z.M., Shioya, H., Ishiko, T., Sun, X., Gu, J., Huang, Y.Y., Lu, H., Kharbanda, S., Weichselbaum, R., Kufe, D., 1999. p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage. Nature, 399(6738):814-817.

[302] Zamzami, N., Kroemer, G., 2001. The mitochondrion in apoptosis: how Pandora’s box opens. Nat. Rev. Mol. Cell Biol., 2(1):67-71.

[303] Zamzami, N., Marchetti, P., Castedo, M., Decaudin, D., Macho, A., Hirsch, T., Susin, S.A., Petit, P.X., Mignotte, B., Kroemer, G., 1995. Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death. J. Exp. Med., 182(2):367-377.

[304] Zamzami, N., Susin, S.A., Marchetti, P., Hirsch, T., Gomez-Monterrey, I., Castedo, M., Kroemer, G., 1996. Mitochondrial control of nuclear apoptosis. J. Exp. Med., 183(4):1533-1544.

[305] Zamzami, N., Brenner, C., Marzo, I., Susin, S.A., Kroemer, G., 1998. Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins. Oncogene, 16(17):2265-2282.

[306] Zeng, Y., Forbes, K.C., Wu, Z., Moreno, S., Piwnica-Worms, H., Enoch, T., 1998. Replication checkpoint requires phosphorylation of the phosphatase Cdc25 by Cds1 or Chk1. Nature, 395(6701):507-510.

[307] Zhan, Q., Antinore, M.J., Wang, X.W., Carrier, F., Smith, M.L., Harris, C.C., Fornace, A.J.Jr, 1999. Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45. Oncogene, 18(18):2892-2900.

[308] Zhang, H., Holzgreve, W., de Geyter, C., 2001. Bcl2-L-10, a novel anti-apoptotic member of the Bcl-2 family, blocks apoptosis in the mitochondria death pathway but not in the death receptor pathway. Hum. Mol. Genet., 10(21):2329-2339.

[309] Zhang, R., Chen, W., Adams, P.D., 2007. Molecular dissection of formation of senescent associated heterochromatin foci. Mol. Cell. Biol., 27(6):2343-2358.

[310] Zinkel, S.S., Hurov, K.E., Ong, C., Abtahi, F.M., Gross, A., Korsmeyer, S.J., 2005. A role for proapoptotic BID in the DNA-damage response. Cell, 122(4):579-591.

[311] Zong, W.X., Edelstein, L.C., Chen, C.L., Bash, J., Gelinas, C., 1999. The prosurvival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-kappaB that blocks TNF alpha-induced apoptosis. Genes. Dev., 13:382-387.

[312] Zoratti, M., Szabo, I., 1995. The mitochondrial permeability transition. Biochim. Biophys. Acta, 1241:139-176.

Open peer comments: Debate/Discuss/Question/Opinion

<1>

Please provide your name, email address and a comment





Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2024 Journal of Zhejiang University-SCIENCE