miR-17 and miR-20a temper an E2F1-induced G1 checkpoint to regulate cell cycle progression

被引:133
作者
Pickering, M. T. [1 ]
Stadler, B. M. [1 ]
Kowalik, T. F. [1 ]
机构
[1] Univ Massachusetts, Dept Mol Genet & Microbiol, Sch Med, Worcester, MA 01605 USA
关键词
checkpoint; DNA damage; E2F1; miRNA; DOUBLE-STRAND BREAKS; E2F1 TRANSCRIPTION FACTOR; GEL-ELECTROPHORESIS; DNA; APOPTOSIS; PHOSPHORYLATION; EXPRESSION; MICRORNAS; ONCOGENE; CANCERS;
D O I
10.1038/onc.2008.372
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 stringent regulation of cell cycle progression helps to maintain genetic stability in cells. MicroRNAs (miRNAs) are critical regulators of gene expression in diverse cellular pathways, including developmental patterning, hematopoietic differentiation and antiviral defense. Here, we show that two c-Myc-regulated miRNAs, miR-17 and miR-20a, govern the transition through G1 in normal diploid human cells. Inhibition of these miRNAs leads to a G1 checkpoint due to an accumulation of DNA double-strand breaks, resulting from premature temporal accumulation of the E2F1 transcription factor. Surprisingly, gross changes in E2F1 levels were not required to initiate the DNA damage response and checkpoint, as these responses could occur with a less than twofold change in E2F1 protein levels. Instead, our findings indicate that the precise timing of E2F1 expression dictates S-phase entry and that accurate timing of E2F1 accumulation requires converging signals from the Rb/E2F pathway and the c-Myc-regulated miR-17 and miR-20a miRNAs to circumvent a G1 checkpoint arising from the untimely accumulation of E2F1. These data provide a mechanistic view of miRNA-based regulation of E2F1 in the context of the emerging model that miRNAs coordinate the timing of cell cycle progression.
引用
收藏
页码:140 / 145
页数:6
相关论文
共 29 条
[1]   DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis [J].
Bartkova, J ;
Horejsi, Z ;
Koed, K ;
Krämer, A ;
Tort, F ;
Zieger, K ;
Guldberg, P ;
Sehested, M ;
Nesland, JM ;
Lukas, C ;
Orntoft, T ;
Lukas, J ;
Bartek, J .
NATURE, 2005, 434 (7035) :864-870
[2]   MicroRNA signatures in human cancers [J].
Calin, George A. ;
Croce, Carlo M. .
NATURE REVIEWS CANCER, 2006, 6 (11) :857-866
[3]  
DEGREGORI J, 1995, MOL CELL BIOL, V15, P4215
[4]   The E2F transcriptional network: old acquaintances with new faces [J].
Dimova, DK ;
Dyson, NJ .
ONCOGENE, 2005, 24 (17) :2810-2826
[5]   Regulation of a senescence checkpoint response by the E2F1 transcription factor and p14ARF tumor suppressor [J].
Dimri, GP ;
Itahana, K ;
Acosta, M ;
Campisi, J .
MOLECULAR AND CELLULAR BIOLOGY, 2000, 20 (01) :273-285
[6]   E2F1 induces MRN foci formation and a cell cycle checkpoint response in human fibroblasts [J].
Frame, F. M. ;
Rogoff, H. A. ;
Pickering, M. T. ;
Cress, W. D. ;
Kowalik, T. F. .
ONCOGENE, 2006, 25 (23) :3258-3266
[7]   An oncogene-induced DNA damage model for cancer development [J].
Halazonetis, Thanos D. ;
Gorgoulis, Vassilis G. ;
Bartek, Jiri .
SCIENCE, 2008, 319 (5868) :1352-1355
[8]   A microRNA polycistron as a potential human oncogene [J].
He, L ;
Thomson, JM ;
Hemann, MT ;
Hernando-Monge, E ;
Mu, D ;
Goodson, S ;
Powers, S ;
Cordon-Cardo, C ;
Lowe, SW ;
Hannon, GJ ;
Hammond, SM .
NATURE, 2005, 435 (7043) :828-833
[9]   E2F1 and E2F3 activate ATM through distinct mechanisms to promote E1A-induced apoptosis [J].
Hong, Sungki ;
Paulson, Qiwei X. ;
Johnson, David G. .
CELL CYCLE, 2008, 7 (03) :391-400
[10]   Sequence-specific inhibition of small RNA function [J].
Hutvágner, G ;
Simard, MJ ;
Mello, CC ;
Zamore, PD .
PLOS BIOLOGY, 2004, 2 (04) :465-475