Document Detail

c-Jun protects hypoxia-inducible factor-1alpha from degradation via its oxygen-dependent degradation domain in a nontranscriptional manner.
MedLine Citation:
PMID:  19738058     Owner:  NLM     Status:  MEDLINE    
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.
Bing Yu; Ze-Hong Miao; Yi Jiang; Mei-Hong Li; Na Yang; Ting Li; Jian Ding
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-09-08
Journal Detail:
Title:  Cancer research     Volume:  69     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2009 Oct 
Date Detail:
Created Date:  2009-10-02     Completed Date:  2009-12-03     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7704-12     Citation Subset:  IM    
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.
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MeSH Terms
Breast Neoplasms / metabolism
Cell Line, Tumor
Endothelial Cells / metabolism
Hela Cells
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Neovascularization, Pathologic / metabolism
Oxygen / metabolism
Proteasome Endopeptidase Complex / metabolism
Protein Structure, Tertiary
Proto-Oncogene Proteins c-jun / genetics,  metabolism*
RNA, Small Interfering / genetics
Transcription, Genetic
Uterine Cervical Neoplasms / metabolism
Reg. No./Substance:
0/HIF1A protein, human; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Proto-Oncogene Proteins c-jun; 0/RNA, Small Interfering; 7782-44-7/Oxygen; EC Endopeptidase Complex; EC 3.4.99.-/ATP dependent 26S protease

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