Interplay between a circadian clock regulator, PER2, and HIF-1

2016 Fiscal Year Final Research Report

• Project/Area Number: 26461886
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Radiation science
• Research Institution: Kyoto University
• Principal Investigator: Morinibu Akiyo 京都大学, 放射線生物研究センター, 研究員 (20722648)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: がん / 低酸素 / 概日リズム

Outline of Final Research Achievements

HIF-1 is a transcription factor functioning in cellular responses to hypoxia. Recent studies have suggested that HIF-1 activity is upregulated by a circadian clock gene, PER2. Here, we analyzed its underlying mechanism in detail. Co-immunoprecipitation experiments and ChIP assay revealed that PER2 interacted with HIF-1α and facilitated the recruitment of HIF-1α to its enhancer, HRE. The PER2-mediated activation of HIF-1 was observed only when HIF-1α N803 was unhydroxylated. However, the extent of PER2-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, PER2 functions as an effector molecule for the recruitment of HIF-1 to promoter regions of its downstream genes. Our findings provide a novel regulatory step in the activation of HIF-1, which can be targeted to develop therapeutic strategies against HIF-1-related diseases, e.g. cancers.

Free Research Field

放射線腫瘍生物学