Journal
PLOS ONE
Volume 8, Issue 4, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0062128
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Funding
- Indian Council of Medical Research [5/3/8/12/2003-RHN]
- Jawaharlal Nehru University
- Department of Science and Technology of India
- Council of Scientific and Industrial Research of India
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Oxygen sensing transcription factor HIF-1 is activated due to accumulation of regulatory subunit HIF-1 alpha by posttranslational stability mechanism during hypoxia or by several other stimuli even in normoxia. HIF-1 alpha is also regulated by NF-kB mediated transcription mechanism. Reactive oxygen species (ROS) act as an important regulator of HIF-1 either by affecting prolyl hydroxylase activity, the critical determinant of HIF-1 alpha stabilization or by activating NF-kB to promote HIF-1 alpha transcription. Insulin is known to activate HIF-1 by a ROS dependent mechanism but the molecular mechanism of HIF-1 alpha regulation is not known so far. Here we show that insulin regulates HIF-1 alpha by a novel transcriptional mechanism by a ROS-sensitive activation of Sp1 in 3T3-L1 preadipocyte. Insulin shows little effect on HIF-1 alpha protein stability, but increases HIF-1 alpha promoter activity. Mutation analyses, electrophoretic mobility shift assay and chromatin immunoprecipitation assay confirm the role of Sp1 in HIF-1 alpha transcription. We further demonstrate that insulin-induced ROS generation initiates signaling pathway involving phosphatidylinositol 3-kinase and protein kinase C for Sp1 mediated HIF-1 alpha transcription. In summary, we reveal that insulin regulates HIF-1 alpha by a novel transcriptional mechanism involving Sp1.
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