Choi Ji-Woong, Park Sang Chul, Kang Gyeong Hoon, Liu Jun O, Youn Hong-Duk
Department of Biochemistry and Molecular Biology, Cancer Research Institute, Seoul, South Korea.
Cancer Res. 2004 Jan 1;64(1):35-9. doi: 10.1158/0008-5472.can-03-0145.
Mutation in the von Hippel-Lindau (VHL) protein associated with renal cell carcinoma causes hypoxia-inducible factor (HIF) to stabilize and consequently to induce various HIF-targeting proteins. In this study, we found that proopiomelanocortin (POMC), an adrenocorticotropic hormone precursor, is up-regulated constitutively in VHL-mutated renal cell carcinoma. A critical transcription factor responsible for POMC overproduction was identified as Nur77, a member of the orphan steroid receptor superfamily. Little is known about how VHL mutation leads to activation of Nur77. We report that Nur77 is directly regulated by HIF. We show that HIF-1alpha, but not HIF-2alpha, binds to a putative HIF responsive element in the Nur77 promoter, activating the expression of Nur77. Mutation or deletion of the HIF binding site in the Nur77 promoter abrogates activation of a luciferase reporter gene under the control of Nur77 promoter by HIF-1alpha. The treatment of Nur77 antisense oligonucleotide reduces POMC transcription under hypoxic conditions. We confirmed that Nur77 and POMC are up-regulated in VHL-mutated renal cell carcinoma. In this study, we provide the first molecular evidence that Nur77 activated by HIF under hypoxic conditions regulates production of the peptide hormone precursor POMC.
与肾细胞癌相关的冯·希佩尔-林道（VHL）蛋白突变会导致缺氧诱导因子（HIF）稳定，进而诱导多种HIF靶向蛋白。在本研究中，我们发现促肾上腺皮质激素前体阿黑皮素原（POMC）在VHL突变的肾细胞癌中持续上调。一种负责POMC过量产生的关键转录因子被确定为孤儿类固醇受体超家族成员Nur77。关于VHL突变如何导致Nur77激活知之甚少。我们报告Nur77直接受HIF调控。我们表明，HIF-1α而非HIF-2α与Nur77启动子中一个假定的HIF反应元件结合，激活Nur77的表达。Nur77启动子中HIF结合位点的突变或缺失消除了HIF-1α对Nur77启动子控制下的荧光素酶报告基因的激活。Nur77反义寡核苷酸处理可降低缺氧条件下POMC的转录。我们证实Nur77和POMC在VHL突变的肾细胞癌中上调。在本研究中，我们提供了首个分子证据，即在缺氧条件下由HIF激活的Nur77调节肽激素前体POMC的产生。
