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c-Jun protects HIF-1a from degradation via its Oxygen-Dependent-Degradation domain in a non-transcriptional manner
Update time: 2009-09-22
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  Bing Yu, Ze-Hong Miao*, Yi Jiang, Mei-Hong Li, Na Yang, Ting Li, Jian Ding*

  Cancer Research (IF 7.514)

  Cancer Res 2009; 69: (19). [Epub ahead of print]

  Although 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 (ODD) domain,masks the sites for ubiquitination, and thus protects HIF-1a from proteasome-executing degradation. All of these together resulted in the stabilization and accumulation of HIF-1a, consequently promoting the transcription of its target gene and driving angiogenesis-related events. The stabilization of HIF-1a was dependent on the domains of c-Jun for DNA binding and heterodimerization, but independent of the Ser63/73 phosphorylation that is critical for transcriptional function. These findings highlight a previously unrecognized non-transcriptional function of c-Jun on the one hand, and a distinct regulatory mechanism of HIF-1a activity on the other, consequently offering profound mechanistic insights into multiple events simultaneously involving both c-Jun and HIF-1a in tumor progression.

 

 

 

 
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