Weber Axel, Marquardt Judith, Elzi David, Forster Nicole, Starke Sven, Glaum Andre, Yamada Daisuke, Defossez Pierre-Antoine, Delrow Jeffrey, Eisenman Robert N, Christiansen Holger, Eilers Martin
Institute of Molecular Biology and Tumour Research (IMT), Marburg, Germany.
EMBO J. 2008 Jun 4;27(11):1563-74. doi: 10.1038/emboj.2008.85. Epub 2008 May 1.
In response to stimuli that activate p53, cells can undergo either apoptosis or cell cycle arrest, depending on the precise pattern of p53 target genes that is activated. We show here that Zbtb4, a transcriptional repressor protein, associates with the Sin3/histone deacetylase co-repressor and represses expression of P21CIP1 as part of a heterodimeric complex with Miz1. In vivo, expression of ZBTB4 is downregulated in advanced stages of multiple human tumours. In cell culture, depletion of ZBTB4 promotes cell cycle arrest in response to activation of p53 and suppresses apoptosis through regulation of P21CIP1, thereby promoting long-term cell survival. Our data suggest that Zbtb4 is a critical determinant of the cellular response to p53 activation and reinforce the notion that p21Cip1 can provide an essential survival signal in cells with activated p53.
作为对激活p53的刺激的反应，细胞可以经历凋亡或细胞周期停滞，这取决于被激活的p53靶基因的精确模式。我们在此表明，转录抑制蛋白Zbtb4与Sin3/组蛋白去乙酰化酶共抑制因子结合，并作为与Miz1的异二聚体复合物的一部分抑制P21CIP1的表达。在体内，ZBTB4的表达在多种人类肿瘤的晚期被下调。在细胞培养中，ZBTB4的缺失促进细胞对p53激活的反应而发生细胞周期停滞，并通过调节P21CIP1抑制凋亡，从而促进细胞的长期存活。我们的数据表明，Zbtb4是细胞对p53激活反应的关键决定因素，并强化了p21Cip1可以在p53激活的细胞中提供重要存活信号的观点。
