MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300
MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300
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DOI：
10.1074/jbc.m209702200
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发表时间：
2003-04-18
影响因子：
4.8
通讯作者：
Caro, J
中科院分区：
文献类型：
--
作者：
Sang, NL;Stiehl, DP;Caro, J
缺氧诱导因子（Hypoxia-inducible factors，HIF）是一类在调节细胞对氧和葡萄糖的利用中起关键作用的异二聚体转录调节因子，是实体瘤和缺血性疾病中血管生成的重要转录调节因子。HIF复合物的反式激活活性需要通过经历氧依赖性降解的HIF-1 α和HIF-2 α募集p300/CREB结合蛋白（CBP）。肿瘤中的HIF活化是由包括丝裂原活化蛋白激酶（MAPK）信号传导在内的多种因素引起的。在这里，我们研究了MAPK激活HIF的分子基础。我们发现MAPK是HIF-1 α转录激活所必需的。此外，MAPK的抑制破坏了HIF-p300的相互作用，并抑制了p300的反式激活活性。MEK 1是一种上游MAPK激活剂，过表达MEK 1可刺激p300和HIF-1 α的反式激活。有趣的是，HIF-1 α的C-末端反式激活结构域不是MAPK的直接底物，并且HIF-1 α磷酸化不是HIFCAD/p300相互作用所必需的。总之，我们的数据表明，MAPK信号通过p300/CBP促进HIF激活。
Hypoxia-inducible factors (HIF) are a family of heterodimeric transcriptional regulators that play pivotal roles in the regulation of cellular utilization of oxygen and glucose and are essential transcriptional regulators of angiogenesis in solid tumor and ischemic disorders. The transactivation activity of HIF complexes requires the recruitment of p300/CREB-binding protein (CBP) by HIF-1alpha and HIF-2alpha that undergo oxygen-dependent degradation. HIF activation in tumors is caused by several factors including mitogen-activated protein kinase (MAPK) signaling. Here we investigated the molecular basis for HIF activation by MAPK. We show that MAPK is required for the transactivation activity of HIF-1alpha. Furthermore, inhibition of MAPK disrupts the HIF-p300 interaction and suppresses the transactivation activity of p300. Overexpression of MEK1, an upstream MAPK activator, stimulates the transactivation of both p300 and HIF-1alpha. Interestingly, the C-terminal transactivation domain of HIF-1alpha is not a direct substrate of MAPK, and HIF-1alpha phosphorylation is not required for HIFCAD/p300 interaction. Taken together, our data suggest that MAPK signaling facilitates HIF activation through p300/CBP.