Nuclear interactor of ARF and Mdm2 regulates multiple pathways to activate p53
Nuclear interactor of ARF and Mdm2 regulates multiple pathways to activate p53
复制标题
DOI：
10.4161/cc.28202
复制
发表时间：
2014-04-15
期刊：
影响因子：
4.3
通讯作者：
Quelle, Dawn E.
中科院分区：
文献类型：
--
作者：
Reed, Sara M.;Hagen, Jussara;Quelle, Dawn E.
p53肿瘤抑制因子受刺激或抑制其转录活性的相互作用因子网络控制。在该网络中，Mdm2通过促进p53的泛素化和降解而成为p53的主要拮抗剂。相反，Tip60通过直接结合靶启动子以及赖氨酸120位点的乙酰化（K120）激活p53。本研究探讨了Mdm2和Tip60与一种新的p53调节因子NIAM （ARF和Mdm2的核相互作用因子）之间的功能关系。先前的研究表明，NIAM可以独立于ARF抑制增殖并激活p53，这表明其他因素介导了这些活性。在这里，我们证明NIAM是一种结合Tip60的染色质相关蛋白。NIAM可以促进p53 K120乙酰化，尽管这种修饰并不需要NIAM抑制增殖或诱导p21启动子的p53反激活。值得注意的是，Tip60沉默表明它有助于niam介导的p53激活，但不是充分的，这表明涉及其他机制。事实上，生长抑制形式的NIAM也与Mdm2结合，NIAM表达水平的增加破坏了p53-Mdm2的结合，抑制了p53多泛素化，并阻止了Mdm2介导的p53转录活性的抑制。重要的是，NIAM的缺失显著损害了p53的激活。总之，这些结果表明NIAM通过多种机制激活p53，包括Tip60关联和Mdm2抑制。因此，NIAM调节了2个控制p53功能的关键通路，并在人类癌症中发生改变，这意味着NIAM在肿瘤发生中起重要作用。
The p53 tumor suppressor is controlled by an interactive network of factors that stimulate or inhibit its transcriptional activity. Within that network, Mdm2 functions as the major antagonist of p53 by promoting its ubiquitylation and degradation. Conversely, Tip60 activates p53 through direct association on target promoters as well as acetylation of p53 at lysine 120 (K120). This study examines the functional relationship between Mdm2 and Tip60 with a novel p53 regulator, NIAM (nuclear interactor of ARF and Mdm2). Previous work showed NIAM can suppress proliferation and activate p53 independently of ARF, indicating that other factors mediate those activities. Here, we demonstrate that NIAM is a chromatin-associated protein that binds Tip60. NIAM can promote p53 K120 acetylation, although that modification is not required for NIAM to inhibit proliferation or induce p53 transactivation of the p21 promoter. Notably, Tip60 silencing showed it contributes to but is not sufficient for NIAM-mediated p53 activation, suggesting other mechanisms are involved. Indeed, growth-inhibitory forms of NIAM also bind to Mdm2, and increased NIAM expression levels disrupt p53-Mdm2 association, inhibit p53 polyubiquitylation, and prevent Mdm2-mediated inhibition of p53 transcriptional activity. Importantly, loss of NIAM significantly impairs p53 activation. Together, these results show that NIAM activates p53 through multiple mechanisms involving Tip60 association and Mdm2 inhibition. Thus, NIAM regulates 2 critical pathways that control p53 function and are altered in human cancers, implying an important role for NIAM in tumorigenesis.