A novel DNA damage checkpoint involving post-transcriptional regulation of cyclin A expression

被引:33
作者
Guo, N [1 ]
Faller, DV [1 ]
Vaziri, C [1 ]
机构
[1] Boston Univ, Sch Med, Ctr Canc Res, Boston, MA 02118 USA
关键词
D O I
10.1074/jbc.275.3.1715
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 intracellular metabolism of many carcinogenic polycyclic aryl hydrocarbons (PAHs, typified by the ubiquitous pollutant benzo[a]pyrene or B[a]P) generates electrophilic products that react covalently with genomic DNA. Cells that acquire PAM-induced DNA damage undergo growth arrest in a p53-independent manner (Vaziri, C,, and Faller, D. V. (1997) J. Biol. Chem. 272, 2762-2769), In this report we have investigated the molecular basis of PAM-induced cell cycle arrest. Mitogenic signaling events involving cyclins D and E, Rb phosphorylation, and transcriptional activation of E2F-responsive genes (including cyclin E and cyclin A) were unaffected in cells containing PAM-damaged DNA. However, PAM-induced growth arrest was associated with post-transcriptional decreases in cyclin A expression. Mitogen-induced expression of cyclin B, an event that is temporally distal to cyclin A expression, was also inhibited in PAM-treated cells. The PAM-induced cell cycle block was transient, and arrested cells resumed DNA synthesis after a prolonged (similar to 20 h) delay. Resumption of DNA synthesis in PAM-treated cells occurred concomitant with elevated expression of cyclins A and B, PAH-induced cell cycle arrest was overcome by ectopically expressed cyclin A (encoded by a recombinant adenovirus in transiently infected cells). Overall, our results suggest the existence of a DNA damage checkpoint pathway that arrests cell cycle progression via post-transcriptional control of cyclin A expression.
引用
收藏
页码:1715 / 1722
页数:8
相关论文
共 29 条
[1]  
BAUM EJ, 1978, POLYCYCLIC HYDROCARB, P45
[2]  
BECKER TC, 1994, METHOD CELL BIOL, V43, P161
[3]   XENOBIOTIC-INDUCIBLE TRANSCRIPTION OF CYTOCHROME-P450 GENES [J].
DENISON, MS ;
WHITLOCK, JP .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (31) :18175-18178
[4]  
Desdouets C, 1995, Prog Cell Cycle Res, V1, P115
[5]   DNA-ADDUCTS OF CHEMICAL CARCINOGENS [J].
DIPPLE, A .
CARCINOGENESIS, 1995, 16 (03) :437-441
[6]   Cell cycle checkpoints: Preventing an identity crisis [J].
Elledge, SJ .
SCIENCE, 1996, 274 (5293) :1664-1672
[7]  
GLOTZER M, 1991, NATURE, V349, P132, DOI 10.1038/349132a0
[8]  
HANKINSON O, 1995, ANNU REV PHARMACOL, V35, P307, DOI 10.1146/annurev.pa.35.040195.001515
[9]   CELL-CYCLE CONTROL AND CANCER [J].
HARTWELL, LH ;
KASTAN, MB .
SCIENCE, 1994, 266 (5192) :1821-1828
[10]   CHEMICAL CARCINOGENESIS [J].
HEIDELBERGER, C .
ANNUAL REVIEW OF BIOCHEMISTRY, 1975, 44 :79-121