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Induction and Testing of Hypoxia in Cell Culture
07:01

Induction and Testing of Hypoxia in Cell Culture

Published on: August 12, 2011

Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling

Maurice Phillip DeYoung1, Peter Horak, Avi Sofer

  • 1Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA.

Genes & Development
|January 17, 2008
PubMed

Insights

Hypoxia inhibits cellular metabolism by affecting the target of rapamycin (TOR) kinase complex 1 (TORC1). REDD1 protein is crucial for this process, regulating TORC1 activity and acting as a tumor suppressor.

Area of Science:

  • Cellular Metabolism
  • Molecular Biology
  • Oncology

Background:

  • Hypoxia significantly alters cellular metabolism via target of rapamycin (TOR) kinase complex 1 (TORC1) inhibition.
  • Tuberous sclerosis tumor suppressors (TSC1/2) and REDD1 protein are vital for hypoxia's regulation of TORC1 activity.

Purpose of the Study:

  • To elucidate the molecular mechanism and physiological significance of hypoxia-induced TORC1 inhibition.
  • To define the role of REDD1 in integrating hypoxia signals for TORC1 regulation.

Main Methods:

  • Investigated the interaction between REDD1, TSC2, and 14-3-3 proteins under hypoxic conditions.
  • Utilized genetic studies with REDD1 and TSC2 mutants in mammalian cells.
  • Assessed cell proliferation and anchorage-independent growth in vitro.
  • Examined tumorigenesis in a mouse model and REDD1 expression in human cancers.

Main Results:

  • Hypoxia and REDD1 suppress mTORC1 activity by dissociating TSC2 from 14-3-3 proteins.
  • Endogenous REDD1 is essential for hypoxia-induced TSC2/14-3-3 dissociation and mTORC1 inhibition.
  • Loss of REDD1 signaling promotes proliferation and anchorage-independent growth under hypoxia.
  • REDD1 deficiency leads to tumorigenesis in vivo, and its downregulation is found in human cancers.

Conclusions:

  • Defined a molecular mechanism where REDD1 facilitates hypoxia-dependent mTORC1 suppression through TSC1/2 regulation.
  • Highlights REDD1's role in a hypoxia-dependent tumor suppressor pathway.
  • Provides insights into cancer development related to hypoxia and REDD1 function.

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