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

• 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)
• Co-Investigator(Kenkyū-buntansha): 吉村 通央 京都大学, 医学研究科, 助教 (40597936) ; 原田 浩 京都大学, 放射線生物研究センター, 教授 (80362531)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: がん / 低酸素 / 概日リズム / HIF-1 / 糖代謝

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.

Research Products

• [Int'l Joint Research] University of Oxford/Imperial College London(UK)
• [Int'l Joint Research] University of Oxford(UK)
• [Journal Article] LY6E: a conductor of malignant tumor growth through modulation of the PTEN/PI3K/Akt/HIF-1 axis. (2016)
  • Author(s): Harada H et al.
  • Journal Title: Oncotargets Volume: 7(40) Pages: 11670-11670
  • DOI: 10.18632/oncotarget.11670
  • NAID: 120005980808
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 1.PLK1 blockade enhances therapeutic effects of radiation by inducing cell cycle arrest at the mitotic phase. (2015)
  • Author(s): Inoue M, Yoshimura M, Kobayashi M, Morinibu A, Itasaka S, Hiraoka M, *Harada H.
  • Journal Title: SCIENTIFIC REPORTS Volume: 5 Pages: 15666-15666
  • DOI: 10.1038/srep15666
  • NAID: 120005753886
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Aberrant IDH3alpha expression promotes malignant tumor growth by inducing HIF-1-mediated metabolic reprogramming and angiogenesis (2015)
  • Author(s): Zeng L, Morinibu A, Kobayashi M, Zhu Y, Wang X, Goto Y, Yeom CJ, Zhao T,Hirota K, Shinomiya K, Itasaka S, Yoshimura M, Guo G, Hammond EM, Hiraoka M, Harada H.
  • Journal Title: Oncogene Volume: epub Pages: 4758-4766
  • DOI: 10.1038/onc.2014.411
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] UCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on ​HIF-1α. (2015)
  • Author(s): Goto Y, Zeng L, YeomCJ, Zhu Y, Morinibu A, Shinoyam K, Kobayashi M, Hirota K, Itasaka S, Yoshimura M, Tanimoto K, Sowa T, Menju T, Sonobe M, Kakeya H, Toi M, Date H, Hammond EM, Hiraoka M, Harada H.
  • Journal Title: Nature communication Volume: 6 Pages: 1-10
  • DOI: 10.1038/ncomms7153
  • NAID: 120005822743
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] HIF-1-mediated metabolic reprogramming reduces ROS levels and facilitates the metastatic colonization of cancers in lungs (2014)
  • Author(s): 1. Zhao T, Zhu Y, Morinibu A, Kobayashi M, Shinomiya K, Itasaka S, Yoshimura M, Guo G, Hiraoka M, Harada H.
  • Journal Title: Scientific reports Volume: 4.3793 Pages: 3793-3793
  • DOI: 10.1038/srep03793
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Remarks] 京都大学放射線生物研究センターがん細胞生物学分野ホームページ
  • URL: http://radiotherapy.kuhp.kyoto-u.ac.jp/biology/
• [Remarks] 京都大学 放射線生物研究センター 原田研究室ホームページ
  • URL: http://radiotherapy.kuhp.kyoto-u.ac.jp/biology/index.html
• [Remarks] 京都大学大学院 医学研究科 放射線腫瘍学・画像応用治療学ホームページ
  • URL: http://radiotherapy.kuhp.kyoto-u.ac.jp/biology/
• [Remarks] Nature Communications誌に掲載された研究成果のプレスリリース（京大ホームページ）
  • URL: http://www.kyoto-u.ac.jp/ja/research/research_results/2014/150113_1.html
• [Remarks] Nature Communications誌に掲載された論文が、「注目の論文」にて紹介されたページ
  • URL: http://www.natureasia.com/ja-jp/ncomms/abstracts/61434