RB regulates transcription of the p21/WAF1/CIP1 gene
RB regulates transcription of the p21/WAF1/CIP1 gene
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DOI：
10.1038/sj.onc.1204169
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发表时间：
2001-02-22
期刊：
影响因子：
8
通讯作者：
Crémisi, CE
中科院分区：
文献类型：
--
作者：
Decesse, JT;Medjkane, S;Crémisi, CE
我们以前已经证明RB在维持上皮表型中起重要作用，p21也参与包括角质形成细胞在内的几种终末分化系统。我们在这里报告，p21是RB的靶基因在上皮细胞，但不是在成纤维细胞，RB是无法反式激活p21的转录表达。在上皮细胞中，当RB家族因子被SV 40 T抗原（LT）灭活时，p21表达被强烈抑制，而当细胞被突变的LT转化时，其表达不受影响，使RB活跃但使p53失活。此外，RB的LT转化上皮细胞的再转化完全恢复了p21的表达。通过共转染实验和使用p21启动子的缺失和点突变，我们表明RB介导的转录激活所需的最小区域映射到位于-83和-74之间的富含GC的区域。该区域显示与转录因子Sp1和Sp3特异性相互作用。因此，我们第一次在上皮细胞中显示RB和p21之间的正转录关系。由于p21保持RB在分化过程中的转录活性的重要hypophosphorylated状态，我们的研究结果意味着RB和p21之间的调节，可能是必不可少的维持分化状态的自动循环。我们认为这种转录关系可能是它们在细胞周期阻滞和几种分化途径中发挥作用所必需的。
We have previously shown that RB plays an important role in the maintenance of the epithelial phenotype, p21 is also involved in several terminal differentiation systems including keratinocytes. We report here that p21 is an RB target gene in epithelial cells, but not in fibroblasts where RB is unable to transactivate p21 transcriptional expression. In epithelial cells, when RB family factors were inactivated by SV40 T antigen (LT), p21 expression was strongly repressed, whereas its expression was not affected when the cells were transformed by a mutated LT leaving RB active but inactivating p53. Moreover, retransformation by RB of LT transformed epithelial cells totally restored p21 expression. By cotransfection experiments and using deletions and point mutations of the p21 promoter, we show that the minimal region required for the RB-mediated transcriptional activation maps to a GC-rich region located between -83 and -74. This region is shown to interact specifically with the transcription factor Sp1 and Sp3. Thus for the first time, we show a positive transcriptional relationship between RB and p21 in epithelial cells. Since p21 keeps RB in a hypophosphorylated state important for its transcriptional activity during differentiation, our results imply an auto-loop of regulation between RB and p21 that may be essential for the maintenance of the differentiation state. We propose that this transcriptional relationship might be necessary of their roles in cell cycle arrest and in several differentiation pathways.