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Hypoxia-Induced
Energy Stress Regulates mRNA Translation and Cell Growth
Liping Liu,1,2
Timothy P. Cash,2
Russell G. Jones,2
Brian Keith,2
Craig B. Thompson,2
and M.
Celeste Simon1,2,
1Howard
Hughes Medical Institute, University of Pennsylvania School of
Medicine, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104
2Abramson
Family Cancer Research Institute, University of Pennsylvania School of
Medicine, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104. Correspondence:
M. Celeste Simon Ph: (215) 746-5532; Fax: (215) 746-5511;
E-mail: celeste2@mail.med.upenn.edu
Received: July 28, 2005. Revised: November 1, 2005. Accepted: January
6, 2006. Published: February 16, 2006.
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Oxygen (O2) deprivation, or
hypoxia, has profound effects on cell metabolism and growth.
Cells can adapt to low O2 in part through activation of
hypoxia-inducible factor (HIF).
We report here that hypoxia inhibits mRNA translation by suppressing
multiple key regulators, including eIF2α, eEF2, and the mammalian
target of rapamycin (mTOR) effectors 4EBP1, p70S6K, and
rpS6, independent of HIF.
Hypoxia results in energy starvation and activation of the AMPK/TSC2/Rheb/mTOR
pathway.
Hypoxic AMP-activated protein kinase (AMPK) activation also leads to
eEF2 inhibition.
Moreover, hypoxic effects on cellular bioenergetics and mTOR
inhibition increase over time.
Mutation of the TSC2 tumor suppressor gene confers a growth advantage
to cells by repressing hypoxic mTOR inhibition and hypoxia-induced G1
arrest.
Together, eIF2α, eEF2, and mTOR inhibition represent important
HIF-independent mechanisms of energy conservation that promote
survival under low O2 conditions.
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