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Kinome siRNA screen identifies SMG-1 as a negative regulator of hypoxia-inducible factor-1alpha in hypoxia

Academic Article
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Overview

authors

  • Chen, R. Q.
  • Yang, Q. K.
  • Chen, Y. L.
  • Oliveira, V. A.
  • Dalton, W. S.
  • Fearns, C.
  • Lee, Jiing-Dwan

publication date

  • June 2009

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Hypoxia-inducible factor-1 (HIF-1) plays a central role in tumor progression by regulating genes involved in proliferation, glycolysis, angiogenesis, and metastasis. To improve our understanding of HIF-1 regulation by kinome, we screened a kinase-specific small interference RNA library using a hypoxia-response element (HRE) luciferase reporter assay under hypoxic conditions. This screen determined that depletion of cellular SMG-1 kinase most significantly modified cellular HIF-1 activity in hypoxia. SMG-1 is the newest and least studied member of the phosphoinositide 3-kinase-related kinase family, which consists of ATM, ATR, DNA-PKcs, mTOR, and SMG-1. We individually depleted members of the phosphoinositide 3-kinase-related kinase family, and only SMG-1 deficiency significantly augmented HIF-1 activity in hypoxia. We subsequently discovered that SMG-1 kinase activity was activated by hypoxia, and depletion of SMG-1 up-regulated MAPK activity under low oxygen. Suppressing cellular MAPK by silencing ERK1/2 or by treatment with U0126, a MAPK inhibitor, partially blocked the escalation of HIF-1 activity resulting from SMG-1 deficiency in hypoxic cells. Increased expression of SMG-1 but not kinase-dead SMG-1 effectively inhibited the activity of HIF-1alpha. In addition, cellular SMG-1 deficiency increased secretion of the HIF-1alpha-regulated angiogenic factor, vascular epidermal growth factor, and survival factor, carbonic anhydrase IX (CA9), as well as promoted the hypoxic cell motility. Taken together, we discovered that SMG-1 negatively regulated HIF-1alpha activity in hypoxia, in part through blocking MAPK activation.

subject areas

  • Antigens, Neoplasm
  • Carbonic Anhydrases
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cell Movement
  • Gene Library
  • HeLa Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • MAP Kinase Signaling System
  • Phosphatidylinositol 3-Kinases
  • Protein Array Analysis
  • Proteome
  • RNA, Small Interfering
  • Vascular Endothelial Growth Factor A
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Identity

PubMed Central ID

  • PMC2719310

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M109.014316

PubMed ID

  • 19406746
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Additional Document Info

start page

  • 16752

end page

  • 16758

volume

  • 284

issue

  • 25

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