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c-Jun Protects Hypoxia-Inducible Factor-1 from Degradation via Its Oxygen-Dependent Degradation Domain in a Nontranscriptional Manner

Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China

Requests for reprints: Jian Ding or Ze-Hong Miao, Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, People's Republic of China. Phone: 86-21-50805897; Fax: 86-21-50806722; E-mail: jding{at}mail.shcnc.ac.cn or zhm{at}jding.dhs.org.

Although hypoxia-inducible factor-1 (HIF-1) has long been intensively investigated as a drug target by interfering with its expression or transcriptional function, the regulatory mechanisms of HIF-1 remain to be further clarified. We report here that c-Jun associates with HIF-1 via its oxygen-dependent degradation domain, masks the sites for ubiquitination, and thus protects HIF-1 from proteasome-executing degradation. All of these together resulted in the stabilization and accumulation of HIF-1, consequently promoting the transcription of its target gene and driving angiogenesis-related events. The stabilization of HIF-1 was dependent on the domains of c-Jun for DNA binding and heterodimerization but independent of the Ser^63/73 phosphorylation that is critical for transcriptional function. These findings highlight a previously unrecognized nontranscriptional function of c-Jun on the one hand and a distinct regulatory mechanism of HIF-1 activity on the other, consequently offering profound mechanistic insights into multiple events simultaneously involving both c-Jun and HIF-1 in tumor progression. [Cancer Res 2009;69(19):7704–12]