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Biol Pharm Bull. 2006 Jan;29(1):49-54.

Transcriptional regulation of the hypoxia inducible factor-2alpha (HIF-2alpha) gene during adipose differentiation in 3T3-L1 cells.

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Department of Health Science, College of Pharmacy, Nihon University, Chiba, Japan.


Adipose differentiation is regulated by coordination of several signaling pathways and transcription factors. We recently showed that Hypoxia inducible factor-2alpha (HIF-2alpha) plays several supporting roles in adipose differentiation and adipocytes functions including regulation of glucose uptake followed by lipid synthesis. HIF-2alpha expression is increased during adipogenesis, indicating that its up-regulation is necessary for execution of adipogenesis and maintenance of mature adipocytes functions. Therefore, in this study, to understand the mechanism by which HIF-2alpha expression is induced during adipogenesis, we investigated the promoter activity of HIF-2alpha gene during adipogenesis in 3T3-L1 cells. A comparison of HIF-2alpha promoter activity between preadipocytes and adipocytes revealed that the sequence -478/-445 is the putative core element that contributes to differentiation-dependent up-regulation of HIF-2alpha promoter activity. Electrophoretic mobility shift assays showed the presence of the specific nuclear factor bound to the sequence -478/-445 in both preadipocytes and adipocytes. Computer analysis revealed that this element contains several Sp1/Sp3 binding sites. Indeed, the presence of Sp1/Sp3 consensus oligonucleotides diminished the formation of the complexes composed of the sequence -478/-445 and the nuclear factor. Furthermore, specific retarded bands were supershifted with anti-Sp1 or -Sp3 antibodies. Binding of Sp1 and Sp3 to this element was also confirmed by chromatin immunoprecipitation analysis. The element encompassing -478/-445 favors Sp3 in preadipocytes and Sp1 in adipocytes. Finally, the activity of -478/-445 was increased by Sp1 but decreased by Sp3. Consequently, these results suggest that Sp1 and Sp3 are involved in transcriptional regulation of HIF-2alpha expression during adipogenesis in 3T3-L1 cells.

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