Control of cell cycle progression by c-Jun is p53 dependent
Control of cell cycle progression by c-Jun is p53 dependent
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DOI：
10.1101/gad.13.5.607
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发表时间：
1999-03-01
影响因子：
10.5
通讯作者：
Wagner, EF
中科院分区：
文献类型：
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作者：
Schreiber, M;Kolbus, A;Wagner, EF
c-jun原癌基因编码丝裂原诱导的立即早期转录因子AP-1的一个组分，并被认为是细胞增殖和G（1）-到-S-期进展的正调节因子。在这里，我们报告说，成纤维细胞来源于c-jun（-/-）小鼠胎儿表现出严重的增殖缺陷，并经历了长期的危机，自发永生化。细胞周期蛋白D1和细胞周期蛋白E依赖性激酶（CDK）和转录因子E2 F活化较差，导致G（1）-S期进展效率低下。此外，c-Tun的缺乏导致肿瘤抑制基因pr 53及其靶基因CDK抑制剂g21的表达升高，而c-Tun的过表达抑制p53和p21表达并加速细胞增殖。令人惊讶的是，蛋白质稳定化，p53调节的共同机制，不参与c-jun（-/-）成纤维细胞中p53的上调。相反，c-Tun通过直接结合p53启动子中的变体AP-1位点来负向调节p53的转录。重要的是，g53的缺失消除了缺乏c-Tun的细胞在细胞周期进展、增殖、永生化和G（1）CDKs和E2 F活化方面的所有缺陷。这些结果表明，在成纤维细胞增殖的c-Tun的一个重要的，限速功能是负调控p53的表达，并建立一个c-Tun依赖的促有丝分裂信号和细胞周期调控之间的机械联系。
The c-jun proto-oncogene encodes a component of the mitogern-inducible immediate-early transcription factor AP-1 and has been implicated as a positive regulator of cell proliferation and G(1)-to-S-phase progression. Here we report that fibroblasts derived from c-jun(-/-) mouse fetuses exhibit a severe proliferation defect and undergo a prolonged crisis before spontaneous immortalization. The cyclin D1- and cyclin E-dependent kinases (CDKs) and transcription factor E2F are poorly activated, resulting in inefficient G(1)-to-S-phase progression. Furthermore, the absence of c-Tun results in elevated expression of the tumor suppressor gene pr53 and its target gene, the CDK inhibitor g21, whereas overexpression of c-Tun represses p53 and p21 expression and accelerates cell proliferation. Surprisingly, protein stabilization, the common mechanism of p53 regulation, is not involved in up-regulation of p53 in c-jun(-/-) fibroblasts. Rather, c-Tun regulates transcription of p53 negatively by direct binding to a variant AP-1 site in the p53 promoter. Importantly, deletion of g53 abrogates all defects of cells lacking c-Tun in cell cycle progression, proliferation, immortalization, and activation of G(1) CDKs and E2F. These results demonstrate that an essential, rate-limiting function of c-Tun in fibroblast proliferation is negative regulation of p53 expression, and establish a mechanistic link between c-Tun-dependent mitogenic signaling and cell-cycle regulation.