PMID- 17179152
OWN - NLM
STAT- MEDLINE
DCOM- 20070618
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 282
IP  - 9
DP  - 2007 Mar 2
TI  - Oxygen tension regulates the stability of insulin receptor substrate-1 (IRS-1) 
      through caspase-mediated cleavage.
PG  - 6090-7
AB  - The insulin and insulin-like growth factor-1 (IGF-1) receptors mediate signaling 
      for energy uptake and growth through insulin receptor substrates (IRSs), which 
      interact with these receptors as well as with downstream effectors. Oxygen is 
      essential not only for ATP production through oxidative phosphorylation but also 
      for many cellular processes, particularly those involved in energy homeostasis. 
      The oxygen tension in vivo is significantly lower than that in the air and can 
      vary widely depending on the tissue as well as on perfusion and oxygen 
      consumption. How oxygen tension affects IRSs and their functions is poorly 
      understood. Our findings indicate that transient hypoxia (1% oxygen) leads to 
      caspase-mediated cleavage of IRS-1 without inducing cell death. The IRS-1 protein 
      level rebounds rapidly upon return to normoxia. Protein tyrosine phosphatases 
      (PTPs) appear to be important for the IRS-1 cleavage because tyrosine 
      phosphorylation of the insulin receptor was decreased in hypoxia and IRS-1 
      cleavage could be blocked either with H(2)O(2) or with vanadate, each of which 
      inhibits PTPs. Activity of Akt, a downstream effector of insulin and IGF-1 
      signaling that is known to suppress caspase activation, was suppressed in 
      hypoxia. Overexpression of dominant-negative Akt led to IRS-1 cleavage even in 
      normoxia, and overexpression of constitutively active Akt partially suppressed 
      IRS-1 cleavage in hypoxia, suggesting that hypoxia-mediated suppression of Akt 
      may induce caspase-mediated IRS-1 cleavage. In conclusion, our study elucidates a 
      mechanism by which insulin and IGF-1 signaling can be matched to the oxygen level 
      that is available to support growth and energy metabolism.
FAU - Kang, Sung Gyun
AU  - Kang SG
AD  - Laboratory of Biochemical Genetics, NHLBI, National Institutes of Health, 
      Bethesda, Maryland 20892, USA.
FAU - Brown, Alexandra L
AU  - Brown AL
FAU - Chung, Jay H
AU  - Chung JH
LA  - eng
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20061219
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (IRS1 protein, human)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Phosphoproteins)
RN  - EC 2.7.10.1 (Receptor, IGF Type 1)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 1)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatases)
RN  - EC 3.4.22.- (Caspases)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Caspases/*metabolism
MH  - Cell Line
MH  - Energy Metabolism
MH  - Humans
MH  - Hypoxia/*metabolism
MH  - Insulin Receptor Substrate Proteins
MH  - Oxygen/*metabolism
MH  - Phosphoproteins/*metabolism
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 1
MH  - Protein Tyrosine Phosphatases/metabolism
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Receptor, IGF Type 1/metabolism
MH  - Signal Transduction
MH  - Transfection
EDAT- 2006/12/21 09:00
MHDA- 2007/06/19 09:00
CRDT- 2006/12/21 09:00
PHST- 2006/12/21 09:00 [pubmed]
PHST- 2007/06/19 09:00 [medline]
PHST- 2006/12/21 09:00 [entrez]
AID - S0021-9258(20)52216-3 [pii]
AID - 10.1074/jbc.M610659200 [doi]
PST - ppublish
SO  - J Biol Chem. 2007 Mar 2;282(9):6090-7. doi: 10.1074/jbc.M610659200. Epub 2006 Dec 
      19.