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首页> 外文期刊>Oncogene >Myc represses differentiation-induced p21CIP1 expression via Miz-1-dependent interaction with the p21 core promoter
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Myc represses differentiation-induced p21CIP1 expression via Miz-1-dependent interaction with the p21 core promoter

机译：Myc通过与p21核心启动子的Miz-1依赖性相互作用抑制分化诱导的p21CIP1表达。

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摘要

Inhibition of cellular differentiation is one of the well-known biological activities of c-Myc-family proteins. We show here that Myc represses differentiation-induced expression of the cyclin-dependent kinase (CDK) inhibitor p21CIP1 (CDKN1A, p21), known to play an important role in cell fate decisions during growth and differentiation, in hematopoietic cells. Our results demonstrate that the c-Myc-responsive region is situated in the p21 core promoter. c-Myc binds to this region in vitro and in vivo through interaction with the initiator-binding Zn-finger transcription factor Miz-1, which associates directly with the promoter. Association of Myc with the promoter in vivo correlates inversely with p21 expression. Using mutants of c-Myc with impaired binding to Miz-1, our results further show that repression of p21 promoter/reporters as well as the endogenous p21 gene by Myc depends on interaction with Miz-1. Expression of Miz-1 increases during hematopoietic differentiation and Miz-1 activates the p21 promoter under conditions of low Myc levels, indicating a positive role for free Miz-1 in this process. In conclusion, repression of differentia-tion-induced p21 expression through Miz-1 may be an important mechanism by which Myc blocks diffe-rentiation.
机译：抑制细胞分化是c-Myc家族蛋白的众所周知的生物学活性之一。我们在这里显示Myc抑制造血细胞中细胞周期蛋白依赖性激酶（CDK）抑制剂p21CIP1（CDKN1A，p21）的分化诱导表达，已知在细胞命运决定过程中起着重要作用。我们的结果证明，c-Myc反应区位于p21核心启动子中。 c-Myc通过与启动子结合的锌指转录因子Miz-1相互作用而在体外和体内与该区域结合，后者直接与启动子结合。 Myc与体内启动子的关联与p21表达成反比。使用与Miz-1结合受损的c-Myc突变体，我们的结果进一步表明Myc抑制p21启动子/报告子以及内源性p21基因取决于与Miz-1的相互作用。在造血分化过程中，Miz-1的表达增加，而在低Myc水平下，Miz-1激活p21启动子，表明游离Miz-1在此过程中具有积极作用。总之，通过Miz-1抑制分化诱导的p21表达可能是Myc阻断差异表达的重要机制。

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