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

Although hypoxia-inducible factor-1α (HIF-1α) has long been intensively investigated as a drug target by interfering with its expression or transcriptional function, the regulatory mechanisms of HIF-1α remain to be further clarified. We report here that c-Jun associates with HIF-1α via its oxygen-dependent degradation domain, masks the sites for ubiquitination, and thus protects HIF-1α from proteasome-executing degradation. All of these together resulted in the stabilization and accumulation of HIF-1α, consequently promoting the transcription of its target gene and driving angiogenesis-related events. The stabilization of HIF-1α 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-1α activity on the other, consequently offering profound mechanistic insights into multiple events simultaneously involving both c-Jun and HIF-1α in tumor progression. [Cancer Res 2009;69(19):7704–12]