E2F transcriptional repressor complexes are critical downstream targets of p19ARF/p53-induced proliferative arrest
E2F transcriptional repressor complexes are critical downstream targets of p19ARF/p53-induced proliferative arrest
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DOI：
10.1016/s1535-6108(02)00085-5
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发表时间：
2002-07-01
期刊：
影响因子：
50.3
通讯作者：
Peeper, DS
中科院分区：
文献类型：
--
作者：
Rowland, BD;Denissov, SG;Peeper, DS
p16（INK 4a）/pRB/E2 F和p19（ARF）/p53肿瘤抑制通路在大多数人类癌症中被破坏。p19（ARF）和p53是诱导原代小鼠胚胎成纤维细胞（MEFs）衰老所必需的，但对其下游靶点知之甚少。在MEFs中E2 F介导的转录抑制的破坏引起E2 F靶基因（包括p19 ARF）表达的普遍增加。我们没有发现E2 F介导的反式激活的贡献，在这种情况下，表明内源性E2 F在异步增长的主要MEFs的主要作用是抑制其靶基因。此外，E2 F对转录抑制的缓解使MEFs对p19（ARF）、p53或RAS（V12）诱导的衰老具有抗性。因此，E2 F转录抑制因子复合物是抗增殖p19（ARF）/p53信号传导的关键下游靶标。
The p16(INK4a)/pRB/E2F and p19(ARF)/p53 tumor suppressor pathways are disrupted in most human cancers. Both p19(ARF) and p53 are required for the induction of senescence in primary mouse embryonic fibroblasts (MEFs), but little is known about their downstream targets. Disruption of E2F-mediated transcriptional repression in MEFs caused a general increase in the expression of E2F target genes, including p19ARF. We detected no contribution of E2F-mediated transactivation in this setting, indicating that a predominant role of endogenous E2F in asynchronously growing primary MEFs is to repress its target genes. Moreover, relief of transcriptional repression by E2F rendered MEFs resistant to senescence induced by either p19(ARF), p53, or RAS(V12). Thus, E2F transcriptional repressor complexes are critical downstream targets of antiproliferative p19(ARF)/p53 signaling.