p53 inhibits hypoxia-inducible factor-stimulated transcription
p53 inhibits hypoxia-inducible factor-stimulated transcription
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DOI：
10.1074/jbc.273.20.11995
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发表时间：
1998-05-15
影响因子：
4.8
通讯作者：
Neckers, L
中科院分区：
文献类型：
--
作者：
Blagosklonny, MV;An, WG;Neckers, L
P53是体内缺氧诱导的细胞凋亡所必需的，尽管其发生的机制尚不清楚。相反，低氧诱导因子-1(HIF-1)反式激活子的诱导刺激了一些对低氧状态的生存至关重要的基因的转录。在这里，我们证明了P53抑制HIF-1刺激的转录。尽管抑制HIF所需的P53水平高于转录激活P53靶基因所需的水平，但这些P53水平类似于刺激多聚(ADP-核糖)聚合酶切割的水平，PDP-核糖聚合酶是细胞凋亡的早期事件，全长p300的转染既刺激P53依赖的转录，也刺激HIF依赖的转录，但不能解除P53介导的对HIF的抑制。相反，p300片段与p53结合，但不与HIF-1结合，阻止了P53依赖的对HIF活性的抑制。在其DNA结合区发生突变的转录失活的p53保留了阻断HIF反式激活活性的能力，而转录失活的p300结合缺陷的双点突变体不抑制HIF。最后，E6蛋白耗尽了阿霉素诱导的内源性P53，减弱了阿霉素对HIF的抑制，这表明在体内可以获得足够抑制HIF的P53水平。这些数据支持一个模型，在该模型中，P53与HIF/p300转录复合体的化学计量结合介导了对HIF活性的抑制。
p53 is required for hypoxia-induced apoptosis in vivo, although the mechanism by which this occurs is not known. Conversely, induction of the hypoxia-inducible factor-1 (HIF-1) transactivator stimulates transcription of a number of genes crucial to survival of the hypoxic state. Here we demonstrate that p53 represses HIF-1-stimulated transcription. Although higher levels of p53 are required to inhibit HIF than are necessary to transcriptionally activate p53 target genes, these levels of p53 are similar to those that stimulate cleavage of poly(ADP-ribose) polymerase, an early event in apoptosis, Transfection of full-length p300 stimulates both p53-dependent and HIF-dependent transcription but does not relieve p53-mediated inhibition of HIF. In contrast, a p300 fragment, which binds to p53 but not to HIF-1, prevents p53-dependent repression of HIF activity. Transcriptionally inactive p53, mutated in its DNA binding domain, retains the ability to block HIF transactivating activity, whereas a transcriptionally inactive double point mutant defective for p300 binding does not inhibit HIF. Finally, depletion of doxorubicin-induced endogenous p53 by E6 protein attenuates doxorubicin-stimulated inhibition of HIF, suggesting that a p53 level sufficient for HIF inhibition can be achieved in vivo. These data support a model in which stoichiometric binding of p53 to a HIF/p300 transcriptional complex mediates inhibition of HIF activity.