Induced p21waf expression in H1299 cell line promotes cell senescence and protects against cytotoxic effect of radiation and doxorubicin

被引：123

作者：

Wang, YC ^{[1
]}

Blandino, G ^{[1
]}

Givol, D ^{[1
]}

机构：

[1] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel

来源：

ONCOGENE | 1999年 / 18卷 / 16期

关键词：

inducible p21(waf); senescence; anti-cancer drugs; radiation;

D O I：

10.1038/sj.onc.1202632

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The CDK inhibitor p21(waf) is a principal mediator of p53 function but can also be transactivated by many p53-independent stimuli leading to cell growth arrest or differentiation. In order to study the function of p21(waf) in a p53-deficient environment, we established an inducible expression of p21(waf) in the p53-null lung cancer cell line H1299, based on the muristerone-regulated system. Overexpression of p211(waf) led cells to growth arrest which after several days became irreversible and the arrested cells acquired a senescent phenotype as judged by cell shape, the senescence-associated beta-gal marker and inhibition of colony formation, The effect of p21(waf) overexpression, in the absence of p53, on the cytotoxicity caused by irradiation, doxorubicin and taxol was studied. Expression of p21(waf) provided protection against the cytotoxic effect of radiation and doxorubicin but not of taxol. These results are relevant to treatment of cancer when p53 is inactive.

引用

页码：2643 / 2649

页数：7

共 34 条

[1] Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts [J].

Alcorta, DA ;

Xiong, Y ;

Phelps, D ;

Hannon, G ;

Beach, D ;

Barrett, JC .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (24) :13742-13747

[2] p53 in signaling checkpoint arrest or apoptosis [J].

Bates, S ;

Vousden, KH .

CURRENT OPINION IN GENETICS & DEVELOPMENT, 1996, 6 (01) :12-18

[3] Bypass of senescence after disruption of p21(CIP1/WAF1) gene in normal diploid human fibroblasts [J].

Brown, JP ;

Wei, WY ;

Sedivy, JM .

SCIENCE, 1997, 277 (5327) :831-834

[4] RADIATION-INDUCED CELL-CYCLE ARREST COMPROMISED BY P21 DEFICIENCY [J].

BRUGAROLAS, J ;

CHANDRASEKARAN, C ;

GORDON, JI ;

BEACH, D ;

JACKS, T ;

HANNON, GJ .

NATURE, 1995, 377 (6549) :552-557

[5]

CHEDID M, 1994, ONCOGENE, V9, P3021

[6] MICE LACKING P21(C/P1/WAF1) UNDERGO NORMAL DEVELOPMENT, BUT ARE DEFECTIVE IN G1 CHECKPOINT CONTROL [J].

DENG, CX ;

ZHANG, PM ;

HARPER, JW ;

ELLEDGE, SJ ;

LEDER, P .

CELL, 1995, 82 (04) :675-684

[7] A BIOMARKER THAT IDENTIFIES SENESCENT HUMAN-CELLS IN CULTURE AND IN AGING SKIN IN-VIVO [J].

DIMRI, GP ;

LEE, XH ;

BASILE, G ;

ACOSTA, M ;

SCOTT, C ;

ROSKELLEY, C ;

MEDRANO, EE ;

LINSKENS, M ;

RUBELJ, I ;

PEREIRASMITH, O ;

PEACOCKE, M ;

CAMPISI, J .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (20) :9363-9367

[8]

ELDEIRY WS, 1993, CELL, V75, P805

[9] Effects of p53 mutations on apoptosis in mouse intestinal and human colonic adenomas [J].

Fazeli, A ;

Steen, RG ;

Dickinson, SL ;

Bautista, D ;

Dietrich, WF ;

Bronson, RT ;

Bresalier, RS ;

Lander, ES ;

Costa, J ;

Weinberg, RA .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (19) :10199-10204

[10]

Gorospe M, 1996, MOL CELL BIOL, V16, P6654

← 1 2 3 4 →