ARF 依赖性调节 ATM 和 p53 相关 KZNF（Apak）蛋白活性以应对致癌应激。

ARF-dependent regulation of ATM and p53 associated KZNF (Apak) protein activity in response to oncogenic stress.

机构信息

State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.

出版信息

FEBS Lett. 2010 Sep 24;584(18):3909-15. doi: 10.1016/j.febslet.2010.08.015. Epub 2010 Aug 14.

DOI:10.1016/j.febslet.2010.08.015

PMID:20713054

Abstract

The KRAB-type zinc-finger protein Apak (ATM and p53 associated KZNF protein) specifically suppresses p53-mediated apoptosis. Upon DNA damage, Apak is phosphorylated and inhibited by ATM kinase, resulting in p53 activation. However, how Apak is regulated in response to oncogenic stress remains unknown. Here we show that upon oncogene activation, Apak is inhibited in the tumor suppressor ARF-dependent but ATM-independent manner. Oncogene-induced ARF protein directly interacts with Apak and competes with p53 to bind to Apak, resulting in Apak dissociation from p53. Thus, Apak is differentially regulated in the ARF and ATM-dependent manner in response to oncogenic stress and DNA damage, respectively.

摘要

KRAB 型锌指蛋白 Apak（ATM 和 p53 相关的 KZNF 蛋白）特异性地抑制 p53 介导的细胞凋亡。在 DNA 损伤时，Apak 被 ATM 激酶磷酸化并抑制，导致 p53 激活。然而，Apak 如何响应致癌应激而被调控仍不清楚。在这里，我们发现，在癌基因激活时，Apak 在肿瘤抑制因子 ARF 依赖性但 ATM 非依赖性方式下被抑制。癌基因诱导的 ARF 蛋白直接与 Apak 相互作用，并与 p53 竞争结合 Apak，导致 Apak 与 p53 解离。因此，Apak 分别以 ARF 和 ATM 依赖性的方式在应对致癌应激和 DNA 损伤时被差异化调控。