Carcinogenesis Advance Access published online on November 16, 2007
Carcinogenesis, doi:10.1093/carcin/bgm262
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CCAAT/enhancer binding protein 
antagonizes transcriptional activity of hypoxia inducible factor-1 with direct protein-protein interaction
1 Institute of Health Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences-Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, CHINA
2 Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, SJTU-SM, Shanghai 200025, CHINA
* To whom correspondence should be addressed at: Department of Pathophysiology, Shanghai Jiao-Tong University School of Medicine. No. 280, Chong-Qing South Road, Shanghai 200025, China. Tel:+86-21-63846590 ext 776573; Fax: +86-21-64154900 Email: chengq{at}shsmu.edu.cn or gqchen{at}sibs.ac.cn
Hypoxia-inducible factor 1 (HIF-1), a master heterodimeric transcriptional regulator consisting of HIF-1
and HIF-1ß subunits for cellular response to hypoxia, plays an important role in carcinogenesis, while CCAAT/enhancer binding protein alpha (C/EBP) is proposed to act as a tumor suppressor in C/EBP-expressing tissues. Previously, we reported that ectopically expressed HIF-1 protein interacts with and enhances transcriptional activity of C/EBP, which favors to leukemic cell differentiation. Here we further showed that such an interaction also occurred in their endogenously expressing state of leukemic U937 cells. GST pull-down assay proposed that the protein-protein interaction was direct, and transactivation domains of C/EBP and the bHLH domain of HIF-1 were essential for such an interaction. More intriguingly, we provided the first demonstration that C/EBP competed with HIF-1ß for direct binding to HIF-1 protein. Correspondingly, C/EBP overexpression significantly inhibited the DNA binding ability of HIF-1 and expressions of hypoxia-responsive element-driven luciferase and HIF-1-targeted genes vascular endothelial growth factor, glucose transporter-1 and phosphoglycerate kinase 1. In parallel, suppression of C/EBP expression by specific small hairpin RNA increased DNA-binding ability of HIF-1 and expression of these HIF-1-targeted genes in leukemic U937 cells. These results would provide new insights for anti-tumor potential of C/EBP protein.
Key Words: hypoxia inducible factor-1 (HIF-1) • CCAAT/enhancer binding protein alpha (C/EBP) • protein-protein interaction • angiogenesis • leukemia
Received August 2, 2007; revised November 5, 2007; accepted November 10, 2007.
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