Amelio Ivano, Inoue Satoshi, Markert Elke K, Levine Arnold J, Knight Richard A, Mak Tak W, Melino Gerry
Medical Research Council Toxicology Unit, Leicester LE1 9HN, United Kingdom;
The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2C1;
Proc Natl Acad Sci U S A. 2015 Jan 6;112(1):226-31. doi: 10.1073/pnas.1410609111. Epub 2014 Dec 22.
Tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) activation are associated with cancer progression. Here, we demonstrate that the transcription factor TAp73 opposes HIF-1 activity through a nontranscriptional mechanism, thus affecting tumor angiogenesis. TAp73-deficient mice have an increased incidence of spontaneous and chemically induced tumors that also display enhanced vascularization. Mechanistically, TAp73 interacts with the regulatory subunit (α) of HIF-1 and recruits mouse double minute 2 homolog into the protein complex, thus promoting HIF-1α polyubiquitination and consequent proteasomal degradation in an oxygen-independent manner. In human lung cancer datasets, TAp73 strongly predicts good patient prognosis, and its expression is associated with low HIF-1 activation and angiogenesis. Our findings, supported by in vivo and clinical evidence, demonstrate a mechanism for oxygen-independent HIF-1 regulation, which has important implications for individualizing therapies in patients with cancer.
肿瘤缺氧和缺氧诱导因子1（HIF-1）激活与癌症进展相关。在此，我们证明转录因子TAp73通过非转录机制对抗HIF-1活性，从而影响肿瘤血管生成。TAp73基因缺陷小鼠自发和化学诱导肿瘤的发生率增加，这些肿瘤也表现出血管生成增强。从机制上讲，TAp73与HIF-1的调节亚基（α）相互作用，并将小鼠双微体2同源物招募到蛋白质复合物中，从而以氧非依赖方式促进HIF-1α多聚泛素化及随后的蛋白酶体降解。在人类肺癌数据集中，TAp73强烈预示患者预后良好，其表达与低HIF-1激活和血管生成相关。我们的发现得到体内和临床证据的支持，证明了一种氧非依赖的HIF-1调节机制，这对癌症患者的个体化治疗具有重要意义。
