An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response
An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response
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DOI：
10.1038/ncb1816
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发表时间：
2009-01-01
影响因子：
21.3
通讯作者：
Schmitz, M. Lienhard
中科院分区：
文献类型：
--
作者：
Calzado, Marco A.;de la Vega, Laureano;Schmitz, M. Lienhard
缺氧（缺氧）导致基因表达模式的重新编程，诱导多方面的细胞反应。在这里，我们确定了丝氨酸/苏氨酸激酶HIPK 2和泛素E3连接酶Siah 2之间的调节相互作用作为控制缺氧反应的机制。在常氧条件下，几种机制确保HIPK 2的稳定性：只有一部分HIPK 2与Siah 2结合，而HIPK 2介导的E3连接酶在26、28和68位的磷酸化削弱了相互结合并使其磷酸化的相互作用伴侣不稳定。低氧条件允许显着增加HIPK 2/Siah 2相互作用，并导致有效的多泛素化和蛋白酶体降解的激酶。因此，缺氧诱导的HIPK 2消除在Siah 2缺陷细胞中显著减少。由于HIPK 2作为基因表达的负调控因子具有重要作用，因此其从启动子相关的阻遏物复合物中的消除允许诱导相当大部分的缺氧诱导基因。
Oxygen deprivation (hypoxia) results in reprogrammed gene expression patterns that induce multifaceted cellular responses. Here we identify a regulated interaction between the serine/threonine kinase HIPK2 and the ubiquitin E3 ligase Siah2 as a mechanism controlling the hypoxic response. Under normoxic conditions, several mechanisms ensure HIPK2 stability: only a fraction of HIPK2 is found in association with Siah2, whereas HIPK2-mediated phosphorylation of this E3 ligase at positions 26, 28 and 68 weakens mutual binding and destabilizes its phosphorylated interaction partner. Hypoxic conditions allow a markedly increased HIPK2/Siah2 interaction and result in efficient polyubiquitylation and proteasomal degradation of the kinase. Accordingly, hypoxia-induced HIPK2 elimination is markedly reduced in Siah2-deficient cells. As HIPK2 has an important role as a negative regulator of gene expression, its elimination from promoter-associated repressor complexes allows the induction of a substantial fraction of hypoxia-induced genes.