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A circadian clock gene, PER 2, activates HIF ‐1 as an effector molecule for recruitment of HIF ‐1α to promoter regions of its downstream genes
Author(s) -
Kobayashi Minoru,
Morinibu Akiyo,
Koyasu Sho,
Goto Yoko,
Hiraoka Masahiro,
Harada Hiroshi
Publication year - 2017
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14280
Subject(s) - effector , pas domain , biology , transcription factor , enhancer , g alpha subunit , microbiology and biotechnology , repressor , hypoxia inducible factor 1 , gene , promoter , protein subunit , gene expression , genetics
Hypoxia‐inducible factor 1 ( HIF ‐1) is a transcription factor functioning in cellular adaptive responses to hypoxia. Recent studies have suggested that HIF ‐1 activity is upregulated by one of the important circadian clock genes, period circadian clock 2 ( PER 2); however, its underlying mechanism remains unclear. Here, we show that PER 2 functions as an effector protein for the recruitment of HIF ‐1α to its cognate enhancer sequence, the hypoxia‐response element ( HRE ). We found that the forced expression of PER 2 enhanced HIF ‐1 activity without influencing expression levels of the regulatory subunit of HIF ‐1, HIF ‐1α, at either mRNA or protein levels. A series of coimmunoprecipitation‐based experiments revealed that PER 2 interacted with HIF ‐1α and facilitated the recruitment of HIF ‐1α to HRE derived from vascular endothelial growth factor ( VEGF ) promoter. The PER 2‐mediated activation of HIF ‐1 was observed only when the asparagine residue at position 803 of HIF ‐1α ( HIF ‐1α N803) was kept unhydroxylated by hypoxic stimulation, by introducing an N803A point mutation, or by an inhibitor of N803‐dioxygenase, deferoxamine. However, the extent of PER ‐2‐ HIF ‐1α interaction was equivalent regardless of the N803 hydroxylation status. Taken together, these results suggest that, with the help of an unknown sensor molecule for the N803 hydroxylation status, PER 2 functions as an effector molecule for the recruitment of HIF ‐1 to promoter regions of its downstream genes. Our findings reveal a novel regulatory step in the activation of HIF ‐1, which can be targeted to develop therapeutic strategies against HIF ‐1‐related diseases, such as cancers.