PMID- 33410354
OWN - NLM
STAT- MEDLINE
DCOM- 20211214
LR  - 20211214
IS  - 1029-2470 (Electronic)
IS  - 1029-2470 (Linking)
VI  - 55
IP  - 2
DP  - 2021 Feb
TI  - Feedback of hypoxia-inducible factor-1alpha (HIF-1alpha) transcriptional activity 
      via redox factor-1 (Ref-1) induction by reactive oxygen species (ROS).
PG  - 154-164
LID - 10.1080/10715762.2020.1870685 [doi]
AB  - Hypoxia-inducible factor-1alpha (HIF-1alpha) is important for adaptation to 
      hypoxia. Hypoxia is a common feature of cancer and inflammation, by which 
      HIF-1alpha increases. However, prolonged hypoxia decreases HIF-1alpha, and the 
      underlying mechanisms currently remain unclear. Cellular reactive oxygen species 
      (ROS) increases in cancer and inflammation. In the present study, we demonstrated 
      that prolonged hypoxia increased ROS, which induced prolyl hydroxylase 
      domain-containing protein 2 (PHD2) and factor inhibiting HIF-1 (FIH-1), major 
      regulators of HIF-1alpha. Cellular stress response (CSR) increased HIF-1alpha 
      transcriptional activity by scavenging endogenous ROS. PHD2 and FIH-1 were 
      induced by external hydrogen peroxide (H(2)O(2)) but were suppressed by 
      ROS-scavenging catalase. We investigated the mechanisms by which PHD2 and FIH-1 
      are regulated by ROS. The knockdown of HIF-1alpha decreased PHD2 and FIH-1 mRNA 
      levels, suggesting their regulation by HIF-1alpha. We then focused on redox 
      factor-1 (Ref-1), which is a regulator of HIF-1alpha transcriptional activity. 
      The knockdown of Ref-1 decreased PHD2 and FIH-1. Ref-1 was regulated by ROS. 
      Prolonged hypoxia and the addition of H(2)O(2) induced the expression of Ref-1. 
      Furthermore, the knockdown of p65, a component of kappa-light-chain enhancer of 
      activated B cells (NF-kappaB), efficiently inhibited the induction of Ref-1 by ROS. 
      Collectively, the present results showed that prolonged hypoxia or increased ROS 
      levels induced Ref-1, leading to the activation of HIF-1alpha transcriptional 
      activity, while the activation of HIF-1alpha via Ref-1 induced PHD2 and FIH-1, 
      causing the feedback of HIF-1alpha. To the best of our knowledge, this is the 
      first study to demonstrate the regulation of HIF-1alpha via Ref-1 by ROS.
FAU - Kobayashi, Yukino
AU  - Kobayashi Y
AD  - Department of Biomedical Chemistry, School of Science and Technology, Kwansei 
      Gakuin University, Sanda, Japan.
FAU - Oguro, Ami
AU  - Oguro A
AD  - Department of Biomedical Chemistry, School of Science and Technology, Kwansei 
      Gakuin University, Sanda, Japan.
AD  - Program of Biomedical Science, Graduate School of Integrated Sciences for Life, 
      Hiroshima University, Hiroshima, Japan.
FAU - Imaoka, Susumu
AU  - Imaoka S
AD  - Department of Biomedical Chemistry, School of Science and Technology, Kwansei 
      Gakuin University, Sanda, Japan.
LA  - eng
PT  - Journal Article
DEP - 20210107
PL  - England
TA  - Free Radic Res
JT  - Free radical research
JID - 9423872
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Reactive Oxygen Species)
SB  - IM
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
MH  - Oxidation-Reduction
MH  - Reactive Oxygen Species/*metabolism
MH  - Signal Transduction
OTO - NOTNLM
OT  - Reactive oxygen species
OT  - cellular stress response
OT  - factor-inhibiting HIF-1
OT  - hypoxia-inducible factor-1alpha
OT  - redox factor-1
EDAT- 2021/01/08 06:00
MHDA- 2021/12/15 06:00
CRDT- 2021/01/07 08:38
PHST- 2021/01/08 06:00 [pubmed]
PHST- 2021/12/15 06:00 [medline]
PHST- 2021/01/07 08:38 [entrez]
AID - 10.1080/10715762.2020.1870685 [doi]
PST - ppublish
SO  - Free Radic Res. 2021 Feb;55(2):154-164. doi: 10.1080/10715762.2020.1870685. Epub 
      2021 Jan 7.