心理压抑
E2F型
视网膜母细胞瘤蛋白
染色质
生物
细胞周期
基因
分子生物学
发起人
细胞生物学
基因表达
遗传学
作者
Michael P. Markey,Steven P. Angus,Matthew W. Strobeck,S. Williams,Ranjaka W. Gunawardena,Bruce J. Aronow,Erik S. Knudsen
出处
期刊:PubMed
日期:2002-11-15
卷期号:62 (22): 6587-97
被引量:45
摘要
The retinoblastoma tumor suppressor, RB, is thought to inhibit cell cycle progression through transcriptional repression. E2F-regulated genes have been viewed as presumptive targets of RB-mediated repression. However, we found that specific E2F targets were not regulated in a consistent manner by the action of a RB allele that is refractory to cyclin-dependent kinase/cyclin-mediated phosphorylation (PSM-RB) when compared with E2F2 overproduction. Therefore, we used Affymetrix GeneChips as an unbiased approach to identify RB targets. We found that expression of PSM-RB significantly attenuates >200 targets, the majority of which are involved in cell cycle control (DNA replication or G2-M), DNA repair, or transcription/chromatin structure. The observed repression was due to the action of RB and not merely a manifestation of altered cell cycle distribution. Additionally, the majority of RB repression targets were confirmed through the blockade of endogenous RB phosphorylation via p16ink4a overexpression. Thus, these results have utility in assigning RB pathway activation in more complex systems of cell cycle inhibition (e.g., mitogen withdrawal, senescence, or DNA damage checkpoint). As expected, a significant fraction of RB-repressed genes have promoters that are bound/regulated by E2F family members. However, targets were identified that are distinct from genes known to be stimulated by overexpression of specific E2F proteins. Moreover, the relative action of RB versus E2F2 overexpression on specific genes demonstrates that a simple opposition model does not explain the relative contribution of RB to gene regulation. Thus, this study provides the first unbiased description of RB-repressed genes, thereby delineating new aspects of RB-mediated transcriptional control and novel targets involved in diverse cellular processes.
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