Che-1-induced inhibition of mTOR pathway enables stress-induced autophagy

EMBO J. 2015 May 5;34(9):1214-30. doi: 10.15252/embj.201489920. Epub 2015 Mar 14.

Abstract

Mammalian target of rapamycin (mTOR) is a key protein kinase that regulates cell growth, metabolism, and autophagy to maintain cellular homeostasis. Its activity is inhibited by adverse conditions, including nutrient limitation, hypoxia, and DNA damage. In this study, we demonstrate that Che-1, a RNA polymerase II-binding protein activated by the DNA damage response, inhibits mTOR activity in response to stress conditions. We found that, under stress, Che-1 induces the expression of two important mTOR inhibitors, Redd1 and Deptor, and that this activity is required for sustaining stress-induced autophagy. Strikingly, Che-1 expression correlates with the progression of multiple myeloma and is required for cell growth and survival, a malignancy characterized by high autophagy response.

Keywords: Che‐1; autophagy; mTOR; multiple myeloma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Autophagy / physiology*
  • Cell Line, Tumor
  • Cell Survival
  • Female
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Mice, Nude
  • Multiple Myeloma / metabolism
  • Multiple Myeloma / pathology*
  • Multiprotein Complexes / metabolism
  • Phosphorylation
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Stress, Physiological
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • AATF protein, human
  • Apoptosis Regulatory Proteins
  • DDIT4 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Multiprotein Complexes
  • Repressor Proteins
  • Transcription Factors
  • DEPTOR protein, human
  • MTOR protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • TOR Serine-Threonine Kinases

Associated data

  • GEO/GSE45009