From top to bottom The two faces of HIPK2 for regulation of the hypoxic response
From top to bottom The two faces of HIPK2 for regulation of the hypoxic response
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DOI：
10.4161/cc.8.11.8597
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发表时间：
2009-06-01
期刊：
影响因子：
4.3
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）触发了一个复杂的信号通路网络，导致基因表达模式的改变，以科普这一挑战。最近的工作已经确定丝氨酸/苏氨酸激酶HIPK 2作为一种新的调节蛋白参与缺氧基因调控。HIPK 2可以影响缺氧反应期间的顶端以及下游事件。在常氧条件下，HIPK 2介导的泛素E3连接酶Siah 2的磷酸化减弱了相互结合并使磷酸化的E3连接酶不稳定。低氧水平导致HIPK 2/Siah 2相互作用强烈增加，从而导致激酶的有效聚泛素化和蛋白酶体降解。在顶端水平，Siah 2抑制磷酸化作用丧失，从而允许Siah 2依赖性的双加氧酶蛋白水解，这又允许转录因子HIF的活化。低氧反应的下游事件受到来自基因抑制复合物的HIPK 2的蛋白酶体消除的影响，这是一种允许完全诱导基因表达的事件。因此，HIPK 2可以调节HIF依赖性和非依赖性基因在缺氧反应的子集。
Oxygen deprivation (hypoxia) triggers a complex network of signaling pathways that result in changed gene expression patterns in order to cope with this challenge. Recent work has identified the serine/threonine kinase HIPK2 as a novel regulatory protein participating in hypoxic gene regulation. HIPK2 can affect apical as well as downstream events during the hypoxic response. Under normoxic conditions, HIPK2-mediated phosphorylation of the ubiquitin E3 ligase Siah2 weakens mutual binding and destabilizes the phosphorylated E3 ligase. Low oxygen levels result in strongly increased HIPK2/Siah2 interactions that lead to efficient polyubiquitylation and proteasomal degradation of the kinase. At the apical level, the Siah2 inhibiting phosphorylations are lost, thus allowing Siah2-dependent proteolysis of dioxygenases which in turn allows for activation of transcription factor HIF. Downstream events of the hypoxic response are affected by the proteasomal elimination of HIPK2 from gene repressing complexes, an event that allows for full induction of gene expression. Thus HIPK2 can regulate a subset of HIF-dependent and -independent genes during the hypoxic response.