DOI: 10.3724/SP.J.1005.2009.00451

Hereditas (Beijing) (遗传) 2009/31:5 PP.451-456

Aging or tumor: the crosstalk between telomerase and p53

Telomerase and p53 play critical roles in tumorigenesis and senescence. The mutation of p53 gene and the reactivation of telomerase have been found in most of the human tumors. Aiming telomerase and p53 genes have become important strategies in tumor therapy. We reviewed the aging and tumor phenotype in different status of telomerase and p53 (mTR-/-p53+/+;mTR-/-p53-/-), which indicated that telomere dysfunction could initiate or suppress the tumorigenesis depending on the status of p53. This helps further understanding of the crosstalk between p53 and telomerase in aging and tumori-genesis, and provides a new idea for treating tumor.

Key words:telomerase,p53,tumorigenesis,aging

ReleaseDate:2014-07-21 14:39:21

[1] Artandi SE, Chang S, Lee SL, Alson S, Gottlieb GJ, Chin L, DePinho RA. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice.Nature, 2000, 406(6796): 641-645.

[2] O'Hagan RC, Chang S, Maser RS, Mohan R, Artandi SE, Chin L, DePinho RA. Telomere dysfunction provokes re-gional amplification and deletion in cancer genomes. Cancer Cell, 2002, 2(2): 149-155.

[3] Stewart SA, Weinberg RA. Telomeres: cancer to human aging. Annu Rev Cell Dev Biol, 2006, 22: 531-557.

[4] Chang S. Modeling aging and cancer in the telomerase knockout mouse. Mutat Res, 2005, 576(1-2): 39-53.

[5] Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O, Peacocke M, Campisi AJ. A biomarker that identifies se-nescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA, 1995, 92(20): 936-39367.

[6] Karlseder J, Broccoli D, Dai Y, Hardy S, de Lange T. p53- and ATM-dependent apoptosis induced by telomeres lack-ing TRF2. Science, 1999, 283(5406): 1321-1325.

[7] Campisi J. Senescent cells, tumor suppression, and organ-ismal aging: good citizens, bad neighbors. Cell, 2005, 120(4): 513-522.

[8] d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, Saretzki G, Carter NP, Jackson SP. A DNA damage checkpoint response in te-lomere-initiated senescence. Nature, 2003, 426(6963): 194-198.

[9] Hastie ND, Dempster M, Dunlop MG, Thompson AM, Green DK, Allshire RC. Telomere reduction in human co-lorectal carcinoma and with ageing. Nature, 1990, 346(6287): 866-868.

[10] Romanov SR, Kozakiewicz BK, Holst CR, Stampfer MR, Haupt LM, Tlsty TD. Normal human mammary epithelial cells spontaneously escape senescence and acquire ge-nomic changes. Nature, 2001, 409(6820): 633-637.

[11] Wong KK, Chang S, Weiler SR, Ganesan S, Chaudhuri J, Zhu C, Artandi SE, Rudolph KL, Gottlieb GJ, Chin L, Alt FW, DePinho RA. Telomere dysfunction impairs DNA re-pair and enhances sensitivity to ionizing radiation. Nat Genet, 2000, 26(1): 85-88.

[12] Samper E, Flores JM, Blasco MA. Restoration of telom-erase activity rescues chromosomal instability and prema-ture aging in Terc-/- mice with short telomeres. EMBO Rep, 2001, 2(9): 800-807.

[13] Lin J, Wu X, Chen J, Chang A, Levine AJ. Functions of the p53 protein in growth regulation and tumor suppression. Cold Spring Harb Symp Quant Biol, 1994, 59: 215-223.

[14] Innocente SA, Abrahamson JL, Cogswell JP, Lee JM. p53 regulates a G2 checkpoint through cyclin B1. Proc Natl Acad Sci USA, 1999, 96(5): 2147-2152.

[15] He G, Siddik ZH, Huang Z, Wang R, Koomen J, Kobaya-shi R, Khokhar AR, Kuang J. Induction of p21 by p53 following DNA damage inhibits both Cdk4 and Cdk2 ac-tivities. Oncogene, 2005, 24(18): 2929-2943.

[16] Fei P, El-Deiry WS. P53 and radiation responses. Oncogene, 2003, 22(37): 5774-5783.

[17] Owen-Schaub LB, Angelo LS, Radinsky R, Ware CF, Gesner TG, Bartos DP. Soluble Fas/APO-1 in tumor cells: a potential regulator of apoptosis? Cancer Lett, 1995, 94(1): 1-8.

[18] Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B. A model for p53-induced apoptosis. Nature, 1997, 389(6648): 300-305.

[19] Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H, Lu X, Soron G, Cooper B, Brayton C, Hee Park S, Thompson T, Karsenty G, Bradley A, Donehower LA. p53 mutant mice that display early ageing-associated phenotypes. Nature, 2002, 415(6867): 45-53.

[20] Efeyan A, Serrano M. p53: guardian of the genome and po-liceman of the oncogenes. Cell Cycle, 2007, 6: 1006-1010.

[21] Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature, 2007, 445(7128): 656-660.

[22] Martins CP, Brown-Swigart L, Evan GI. Modeling the therapeutic efficacy of p53 restoration in tumors. Cell, 2006, 127(7): 1323-1334.

[23] Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, Newman J, Reczek EE, Weissleder R, Jacks T. Restoration of p53 function leads to tumour re-gression in vivo. Nature, 2007, 445(7128): 661-665.

[24] Chin L, Artandi SE, Shen Q, Tam A, Lee SL, Gottlieb GJ, Greider CW, DePinho RA. p53 deficiency rescues the ad-verse effects of telomere loss and cooperates with te-lomere dysfunction to accelerate carcinogenesis. Cell, 1999, 97(4): 527-538.

[25] Rudolph KL, Chang S, Lee HW, Blasco M, Gottlieb GJ, Greider C, DePinho RA. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell, 1999, 96(5): 701-712.

[26] Lee HW, Blasco MA, Gottlieb GJ, Horner JW, 2nd, Grei-der CW, DePinho RA. Essential role of mouse telomerase in highly proliferative organs. Nature, 1998, 392(6676): 569-574.

[27] Lee KH, Rudolph KL, Ju YJ, Greenberg RA, Cannizzaro L, Chin L, Weiler SR, DePinho RA. Telomere dysfunction alters the chemotherapeutic profile of transformed cells. Proc Natl Acad Sci USA, 2001, 98(6): 3381-3386.

[28] Liu G, Parant JM, Lang G, Chau P, Chavez-Reyes A, El-Naggar AK, Multani A, Chang S, Lozano G. Chromo-some stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice. Nat Genet, 2004, 36(1): 63-68.

[29] Cosme-Blanco W, Shen MF, Lazar AJ, Pathak S, Lozano G, Multani AS, Chang S. Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53-dependent cellular senescence. EMBO Rep, 2007, 8(5): 497-503.

[30] Beliveau A, Yaswen P. Soothing the watchman: telomerase reduces the p53-dependent cellular stress response. Cell Cycle, 2007, 6(11): 1284-1287.