The Fanconi anemia group C gene product modulates apoptotic responses to tumor necrosis factor-alpha and Fas ligand but does not suppress expression of receptors of the tumor necrosis factor receptor superfamily

Exp Hematol. 1999 Jan;27(1):1-8. doi: 10.1016/s0301-472x(98)00064-2.

Abstract

Exposure of hematopoietic progenitor cells (HPC) from mice and humans with Fanconi anemia group C (FAC) to interferon-gamma (IFN-gamma) or tumor necrosis factor-alpha (TNF-alpha) at doses too low to inhibit growth of normal HPC induces profound apoptotic responses. Because the IFN-gamma hypersensitivity of cells lacking the FAC protein is mediated, in part, through priming of the Fas pathway, and because several other members of this family are capable of inducing apoptosis either alone or in concert with each other, we tested the hypothesis that IFN-gamma induces increased expression of members of the TNF receptor (TNFR) superfamily in cells nullizygous for the FAC gene. Using isogenic human Epstein-Barr virus-transformed lymphoblast cell lines and c-kit+ bone marrow cells from mice with inactivating mutations of the FAC locus, we quantified mRNA levels by reverse transcriptase polymerase chain reaction and surface expression of the gene products by flow cytometry of TNFR1, TNFR2, Fas, CD30, CD40, and nerve growth factor receptor. We found that neither constitutive nor IFN-gamma-induced expression of these receptors was influenced by the absence of a functional FAC gene product, and expression of these receptors was not suppressed in nullizygous cells complemented with the normal FAC cDNA. We conclude that, although exaggerated apoptotic responses in FAC-deficient cells are at least partially mediated through activation of members of the TNFR superfamily, the normal FAC protein does not function as a direct suppressor of this family of molecules and inactivation of FAC does not augment expression of these proteins.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Cell Cycle Proteins*
  • Cell Line, Transformed
  • DNA-Binding Proteins*
  • Fanconi Anemia Complementation Group C Protein
  • Fanconi Anemia Complementation Group Proteins
  • Fas Ligand Protein
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Interferon-gamma / pharmacology
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Proteins*
  • Proteins / physiology*
  • RNA, Messenger / analysis
  • Receptors, Tumor Necrosis Factor / biosynthesis*
  • Receptors, Tumor Necrosis Factor / genetics
  • Signal Transduction
  • Tumor Cells, Cultured / metabolism
  • Tumor Cells, Cultured / pathology
  • Tumor Necrosis Factor-alpha / physiology*

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • FANCC protein, human
  • FASLG protein, human
  • Fancc protein, mouse
  • Fanconi Anemia Complementation Group C Protein
  • Fanconi Anemia Complementation Group Proteins
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Membrane Glycoproteins
  • Nuclear Proteins
  • Proteins
  • RNA, Messenger
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma