Claassen G F, Hann S R
Department of Cell Biology, School of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9498-503. doi: 10.1073/pnas.150006697.
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 (TGFbeta) treatment of immortalized human keratinocyte cells inhibits cell-cycle progression and is characterized by down-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 TGFbeta treatment. The induction of p21(CIP1) transcription by TGFbeta was blocked in human keratinocyte cells stably expressing c-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 TGFbeta 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.
c-Myc在细胞周期进程中起着至关重要的作用。c-Myc的表达失调可克服细胞周期停滞，从而促进细胞增殖。用转化生长因子β（TGFβ）处理永生化的人角质形成细胞会抑制细胞周期进程，其特征是c-Myc下调，随后p21（CIP1）上调。c-Myc在该途径中的直接作用通过以下观察得以证明：c-Myc的异位表达克服了TGFβ处理诱导的细胞周期阻滞。在稳定表达c-Myc的人角质形成细胞中，TGFβ诱导的p21（CIP1）转录被阻断。此外，在NIH 3T3细胞中过表达c-Myc可抑制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位点附近区域的启动子水平，且与组蛋白脱乙酰酶活性无关。这些数据表明，TGFβ信号传导后c-Myc的下调对于随后p21（CIP1）的调节和细胞周期抑制很重要。因此，细胞周期抑制基因p21（CIP1）的抑制在c-Myc依赖的细胞周期进程中起作用。
