p53 checkpoint-defective cells are sensitive to X rays, but not hypoxia

被引:20
作者
Denko, NC [1 ]
Green, SL [1 ]
Edwards, D [1 ]
Giaccia, AJ [1 ]
机构
[1] Stanford Univ, Div Radiat Biol, Sch Med, Dept Radiat Oncol,Mayer Canc Biol Lab, Stanford, CA 94305 USA
关键词
tumor microenvironment; cell-cycle arrest; p21; genomic instability; apoptosis;
D O I
10.1006/excr.2000.4928
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
X-ray-induced damage leads to cell-cycle "checkpoint" arrest by p53-dependent induction of the cyclin-dependent kinase inhibitor p21 (Waf1/Cip1/Sdi1). Human tumor cells that lack this response fail to arrest after exposure to DNA-damaging agents, undergo multiple rounds of endoreduplicative DNA synthesis, and eventually commit to an apoptotic cell death. Since low oxygen tension can also induce p53 protein accumulation, and can lead to cell-cycle arrest or apoptosis, we examined the expression of p21 in tumor cells under normoxic and hypoxic conditions. In a survey of cells, mRNA for the p21 gene was induced two- to threefold in response to hypoxia in a seemingly p53-independent manner. We therefore examined genetically matched cells that differ in their p21 and p53 status for response to ionizing radiation and hypoxia. We found that both pal-deficient and p53-deficient cells exhibit an increase in chromosome instability, an increased level of apoptosis, and a failure to arrest after exposure to ionizing radiation. However, cells that lack either p21 or p53 exhibit no increase in chromosome instability or elevated apoptosis and still arrest in response to hypoxia. Thus, the mechanism responsible for the differential response to either hypoxia or X rays presumably lies in the control of cell-cycle progression in response to stress and its dependence on p21. Since the loss of a DNA-damage-dependent checkpoint does not sensitize cells to killing by stresses that elicit a DNA-damage-independent checkpoint, targeting the function of p21 pharmacologically will not kill tumor cells in situ in the absence of a DNA damage signal. (C) 2000 Academic Press.
引用
收藏
页码:82 / 91
页数:10
相关论文
共 40 条
[1]  
Alarcon RM, 1996, CANCER RES, V56, P4315
[2]   CELL INACTIVATION AND CELL-CYCLE INHIBITION AS INDUCED BY EXTREME HYPOXIA - THE POSSIBLE ROLE OF CELL-CYCLE ARREST AS A PROTECTION AGAINST HYPOXIA-INDUCED LETHAL DAMAGE [J].
AMELLEM, O ;
PETTERSEN, EO .
CELL PROLIFERATION, 1991, 24 (02) :127-141
[3]   Apoptosis inhibitory activity of cytoplasmic p21Cip1/WAF1 in monocytic differentiation [J].
Asada, M ;
Yamada, T ;
Ichijo, H ;
Delia, D ;
Miyazono, K ;
Fukumuro, K ;
Mizutani, S .
EMBO JOURNAL, 1999, 18 (05) :1223-1234
[4]   p21-induced cycle arrest in G1 protects cells from apoptosis induced by UV-irradiation or RNA polymerase II blockage [J].
Bissonnette, N ;
Hunting, DJ .
ONCOGENE, 1998, 16 (26) :3461-3469
[5]  
Brown JM, 1998, CANCER RES, V58, P1408
[6]   Requirement for p53 and p21 to sustain G2 arrest after DNA damage [J].
Bunz, F ;
Dutriaux, A ;
Lengauer, C ;
Waldman, T ;
Zhou, S ;
Brown, JP ;
Sedivy, JM ;
Kinzler, KW ;
Vogelstein, B .
SCIENCE, 1998, 282 (5393) :1497-1501
[7]   Activation of the ATM kinase by ionizing radiation and phosphorylation of p53 [J].
Canman, CE ;
Lim, DS ;
Cimprich, KA ;
Taya, Y ;
Tamai, K ;
Sakaguchi, K ;
Appella, E ;
Kastan, MB ;
Siliciano, JD .
SCIENCE, 1998, 281 (5383) :1677-1679
[8]   Role of HIF-1α or in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis [J].
Carmeliet, P ;
Dor, Y ;
Herbert, JM ;
Fukumura, D ;
Brusselmans, K ;
Dewerchin, M ;
Neeman, M ;
Bono, F ;
Abramovitch, R ;
Maxwell, P ;
Koch, CJ ;
Ratcliffe, P ;
Moons, L ;
Jain, RK ;
Collen, D ;
Keshet, E .
NATURE, 1998, 394 (6692) :485-490
[9]   Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis (vol 394, pg 485, 1998) [J].
Carmeliet, P ;
Dor, Y ;
Herbert, JM ;
Fukumura, D ;
Brusselmans, K ;
Dewerchin, M ;
Neeman, M ;
Bono, F ;
Abramovitch, R ;
Maxwell, P ;
Koch, CJ ;
Ratcliffe, P ;
Moons, L ;
Jain, RK ;
Collen, D ;
Keshert, E .
NATURE, 1998, 395 (6701) :525-525
[10]   p53 levels, functional domains, and DNA damage determine the extent of the apoptotic response of tumor cells [J].
Chen, XB ;
Ko, LJ ;
Jayaraman, L ;
Prives, C .
GENES & DEVELOPMENT, 1996, 10 (19) :2438-2451