PMID- 19098000
OWN - NLM
STAT- MEDLINE
DCOM- 20090413
LR  - 20211203
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 284
IP  - 8
DP  - 2009 Feb 20
TI  - The Akt/mTOR pathway assures the synthesis of HIF-1alpha protein in a glucose- 
      and reoxygenation-dependent manner in irradiated tumors.
PG  - 5332-42
LID - 10.1074/jbc.M806653200 [doi]
AB  - Transcriptional activity of HIF-1 (hypoxia-inducible factor-1) has been reported 
      to be up-regulated in solid tumors after ionizing radiation; however, the 
      molecular mechanism underlying the response remains to be elucidated. In the 
      present study, we performed a series of molecular imaging experiments using a 
      HIF-1-dependent reporter gene, 5HREp-ODD-luc, and found an essential role of the 
      Akt/mTOR pathway. Hypoxic tumor cells distant from blood vessels were 
      dramatically reoxygenated at 24 h postirradiation, and HIF-1 activity increased 
      as HIF-1alpha accumulated in the reoxygenated regions. The accumulation was 
      inhibited with a nonmetabolizable glucose analog, 2-deoxy-d-glucose, through the 
      suppression of radiation-induced phosphorylation of Akt in the reoxygenated 
      regions. Akt knockdown and an mTOR inhibitor revealed the importance of the 
      Akt/mTOR pathway in the postirradiation accumulation of HIF-1alpha. In vitro 
      experiments confirmed that an increase in glucose availability induced Akt 
      phosphorylation under reoxygenated conditions and consequently up-regulated 
      HIF-1alpha translation. Moreover, both the accelerated translation and the 
      previously reported reactive oxygen species-mediated stabilization of HIF-1alpha 
      protein were essential to the activation of HIF-1. All of these results indicate 
      that Akt/mTOR-dependent translation of HIF-1alpha plays a critical role in the 
      postirradiation up-regulation of intratumoral HIF-1 activity in response to 
      radiation-induced alterations of glucose and oxygen availability in a solid 
      tumor.
FAU - Harada, Hiroshi
AU  - Harada H
AD  - Department of Radiation Oncology and Image-applied Therapy, Kyoto University 
      Graduate School of Medicine, Kyoto, Japan. hharada@kuhp.kyoto-u.ac.jp
FAU - Itasaka, Satoshi
AU  - Itasaka S
FAU - Kizaka-Kondoh, Shinae
AU  - Kizaka-Kondoh S
FAU - Shibuya, Keiko
AU  - Shibuya K
FAU - Morinibu, Akiyo
AU  - Morinibu A
FAU - Shinomiya, Kazumi
AU  - Shinomiya K
FAU - Hiraoka, Masahiro
AU  - Hiraoka M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20081219
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - IY9XDZ35W2 (Glucose)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Animals
MH  - Cell Hypoxia/radiation effects
MH  - *Gamma Rays
MH  - Glucose/*metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*biosynthesis/genetics/*metabolism
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Neoplasms/genetics/*metabolism/pathology
MH  - Oxygen/metabolism
MH  - Oxygen Consumption/radiation effects
MH  - Protein Biosynthesis/radiation effects
MH  - Protein Kinases/genetics/*metabolism
MH  - Protein Stability/radiation effects
MH  - Proto-Oncogene Proteins c-akt/genetics/*metabolism
MH  - TOR Serine-Threonine Kinases
EDAT- 2008/12/23 09:00
MHDA- 2009/04/14 09:00
CRDT- 2008/12/23 09:00
PHST- 2008/12/23 09:00 [entrez]
PHST- 2008/12/23 09:00 [pubmed]
PHST- 2009/04/14 09:00 [medline]
AID - S0021-9258(20)70992-0 [pii]
AID - 10.1074/jbc.M806653200 [doi]
PST - ppublish
SO  - J Biol Chem. 2009 Feb 20;284(8):5332-42. doi: 10.1074/jbc.M806653200. Epub 2008 
      Dec 19.