Fanconi anemia group C protein prevents apoptosis in hematopoietic cells through redox regulation of GSTP1

  • Cumming R
  • Lightfoot J
  • Beard K
 et al. 
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Abstract

The Fanconi anemia group C protein (FANCC) plays an important role in hematopoiesis by ensuring the survival of hematopoietic progenitor cells through an unknown mechanism. We investigated the function of FANCC by identifying FANCC-binding proteins in hematopoietic cells. Here we show that glutathione S-transferase P1-1 (GSTP1) interacts with FANCC, and that overexpression of both proteins in a myeloid progenitor cell line prevents apoptosis following factor deprivation. FANCC increases GSTP1 activity after the induction of apoptosis. GSTP1 is an enzyme that catalyzes the detoxification of xenobiotics and by-products of oxidative stress, and it is frequently upregulated in neoplastic cells. Although FANCC lacks homology with conventional disulfide reductases, it functions by preventing the formation of inactivating disulfide bonds within GSTP1 during apoptosis. The prevention of protein oxidation by FANCC reveals a novel mechanism of enzyme regulation during apoptosis and has implications for the treatment of degenerative diseases with thiol reducing agents.

Author-supplied keywords

  • *Cell Cycle Proteins
  • *DNA-Binding Proteins
  • *Nuclear Proteins
  • Apoptosis/*physiology
  • Catalysis
  • Cell Line
  • Fanconi Anemia Complementation Group C Protein
  • Fanconi Anemia Complementation Group Proteins
  • Genetic Vectors
  • Glutathione S-Transferase pi
  • Glutathione Transferase/genetics/*metabolism
  • Glutathione/physiology
  • Hematopoietic Stem Cells/*cytology
  • Humans
  • Isoenzymes/genetics/*metabolism
  • Oxidation-Reduction
  • Proteins/*physiology
  • Retroviridae/genetics

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Authors

  • R C Cumming

  • J Lightfoot

  • K Beard

  • H Youssoufian

  • P J O'Brien

  • M Buchwald

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