alexa Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha.
Genetics & Molecular Biology

Genetics & Molecular Biology

Journal of Molecular Biomarkers & Diagnosis

Author(s): Koumenis C, Naczki C, Koritzinsky M, Rastani S, Diehl A,

Abstract Share this page

Abstract Hypoxia profoundly influences tumor development and response to therapy. While progress has been made in identifying individual gene products whose synthesis is altered under hypoxia, little is known about the mechanism by which hypoxia induces a global downregulation of protein synthesis. A critical step in the regulation of protein synthesis in response to stress is the phosphorylation of translation initiation factor eIF2alpha on Ser51, which leads to inhibition of new protein synthesis. Here we report that exposure of human diploid fibroblasts and transformed cells to hypoxia led to phosphorylation of eIF2alpha, a modification that was readily reversed upon reoxygenation. Expression of a transdominant, nonphosphorylatable mutant allele of eIF2alpha attenuated the repression of protein synthesis under hypoxia. The endoplasmic reticulum (ER)-resident eIF2alpha kinase PERK was hyperphosphorylated upon hypoxic stress, and overexpression of wild-type PERK increased the levels of hypoxia-induced phosphorylation of eIF2alpha. Cells stably expressing a dominant-negative PERK allele and mouse embryonic fibroblasts with a homozygous deletion of PERK exhibited attenuated phosphorylation of eIF2alpha and reduced inhibition of protein synthesis in response to hypoxia. PERK(-/-) mouse embryo fibroblasts failed to phosphorylate eIF2alpha and exhibited lower survival after prolonged exposure to hypoxia than did wild-type fibroblasts. These results indicate that adaptation of cells to hypoxic stress requires activation of PERK and phosphorylation of eIF2alpha and suggest that the mechanism of hypoxia-induced translational attenuation may be linked to ER stress and the unfolded-protein response.
This article was published in Mol Cell Biol and referenced in Journal of Molecular Biomarkers & Diagnosis

Relevant Expert PPTs

Relevant Speaker PPTs

Recommended Conferences

  • 9th International Conference and Expo on Molecular & Cancer Biomarkers
    August 23-24, 2017 Birmingham, UK
  • 2nd International Conference on Medical Imaging and Diagnosis
    London, UK
  • 22nd International Conference on Cancer Drugs and Therapeutics
    Paris, France
  • International Conference on Oncology Nursing and Cancer Care
    Singapore City, Singapore
  • World Summit on Cell Signalling and Cancer Therapy
    Toronto, Canada
  • International Conference on Radiology and Imaging
    New York, USA

Relevant Topics

Peer Reviewed Journals
 
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
International Conferences 2017-18
 
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

 
© 2008-2017 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version
adwords