c-Jun protects hypoxia-inducible factor-1alpha from degradation via its oxygen-dependent degradation domain in a nontranscriptional manner.

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