A role for transcriptional repression of p21CIP1 by c-Myc in overcoming transforming growth factor β-induced cell-cycle arrest
A role for transcriptional repression of p21CIP1 by c-Myc in overcoming transforming growth factor β-induced cell-cycle arrest
复制标题
DOI：
10.1073/pnas.150006697
复制
发表时间：
2000-08-15
影响因子：
11.1
通讯作者：
Hann, SR
中科院分区：
文献类型：
--
作者：
Claassen, GF;Hann, SR
C-Myc在细胞周期进程中起着至关重要的作用，c-Myc的失控表达可以克服细胞周期停滞，从而促进细胞增殖。转化生长因子-β(TCF-β)处理永生化人角质形成细胞可抑制细胞周期进程，其特点是先上调c-Myc，再上调p21(CIP1)。C-Myc的异位表达克服了转化生长因子β诱导的细胞周期阻滞。在稳定表达E-Myc的角质形成细胞中，转化生长因子β对p21(CIP1)转录的诱导被阻断，而且c-Myc在NIH3T3细胞中的过表达抑制了p21(CIP1)mRNA的基础水平。C-Myc对p21(CIP1)转录的抑制发生在转录起始点附近的启动子水平，与组蛋白脱乙酰酶活性无关。这些数据表明，转化生长因子β信号转导后c-Myc的下调对随后的p21(CIP1)调控和细胞周期抑制具有重要意义。因此，抑制细胞周期抑制基因p21(CIP1)在c-Myc依赖的细胞周期进程中发挥作用。
c-Myc plays a vital role in cell-cycle progression, Deregulated expression of c-Myc can overcome cell-cycle arrest in order to promote cellular proliferation. Transforming growth factor beta (TCF beta) treatment of immortalized human keratinocyte cells inhibits cell-cycle progression and is characterized by dawn-regulation of c-Myc followed by up-regulation of p21(CIP1). A direct role of c-Myc in this pathway was demonstrated by the observation that ectopic expression of c-Myc overcame the cell-cycle block induced by TGF beta treatment The induction of p21(CIP1) transcription by TGF beta was blocked in human keratinocyte cells stably expressing E-Myc, Furthermore, overexpression of c-Myc in NIH 3T3 cells repressed the basal levels of p21(CIP1) mRNA. Repression of p21(CIP1) transcription by c-Myc occurred at the promoter level in a region near the start site of transcriptional initiation and was independent of histone deacetylase activity. These data suggest that the down-regulation of c-Myc after TGF beta signaling is important for subsequent regulation of p21(CIP1) and cell-cycle inhibition. Thus, repression of the cell-cycle inhibitory gene p21(CIP1) plays a role in c-Myc-dependent cell-cycle progression.