AP4 encodes a c-MYC-inducible repressor of p21
AP4 encodes a c-MYC-inducible repressor of p21
复制标题
DOI：
10.1073/pnas.0801773105
复制
发表时间：
2008-09-30
影响因子：
11.1
通讯作者：
Hermeking, Heiko
中科院分区：
文献类型：
--
作者：
Jung, Peter;Menssen, Antje;Hermeking, Heiko
在大多数人类肿瘤中，c-MYC癌基因的表达变为组成型。在这里，我们报告说，c-MYC直接调节AP 4的表达，通过CACGTG基序在AP 4基因的第一个内含子。诱导AP 4是c-MYC介导的抗雌激素阻滞的乳腺癌细胞的细胞周期再进入和有丝分裂原介导的CDK抑制剂p21的抑制所必需的。AP 4通过其碱性区占据p21启动子中的四个CAGCTG基序直接抑制p21。DNA损伤后AP 4水平下降，异位AP 4干扰p53介导的细胞周期阻滞，并使细胞对DNA损伤剂诱导的凋亡敏感。AP 4的表达阻断了人角质形成细胞中TGF-β对p21的诱导，并干扰了单核细胞分化过程中p21的上调和细胞周期停滞。值得注意的是，AP 4在结肠祖细胞和结肠直肠癌细胞中特异性表达。总之，我们的研究结果表明，c-MYC利用AP 4来维持细胞处于增殖的祖细胞样状态。
In the majority of human tumors, expression of the c-MYC oncogene becomes constitutive. Here, we report that c-MYC directly regulates the expression of AP4 via CACGTG motifs in the first intron of the AP4 gene. Induction of AP4 was required for c-MYC-mediated cell cycle reentry of anti-estrogen arrested breast cancer cells and mitogen-mediated repression of the CDK inhibitor p21. AP4 directly repressed p21 by occupying four CAGCTG motifs in the p21 promoter via its basic region. AP4 levels declined after DNA damage, and ectopic AP4 interfered with p53-mediated cell cycle arrest and sensitized cells to apoptosis induced by DNA damaging agents. AP4 expression blocked induction of p21 by TGF-beta in human keratinocytes and interfered with up-regulation of p21 and cell cycle arrest during monoblast differentiation. Notably, AP4 is specifically expressed in colonic progenitor and colorectal carcinoma cells. In conclusion, our results indicate that c-MYC employs AP4 to maintain cells in a proliferative, progenitor-like state.