The fanconi anemia group c gene product modulates apoptotic responses to tumor necrosis factor receptor superfamily proteins but does not suppress expression of these receptors

P. S. Koh, G. G. Hughes, G. R. Faulkner, W. W. Keeble, G. C. Baobv

Research output: Contribution to journalArticlepeer-review

Abstract

Exposure of hematopoietic progenitor cells (HPC) from mice and humans with Fanconi anemia group C (FAC) to interferon-y (IFN-y) or tumor necrosis factor-a (TNF-a) at doses too low to inhibit growth of normal HPC induces apoptotic responses. Because the IFN-y hypersensitivity of cells lacking the FAC gene product is mediated in part through priming of the Fas pathway, we tested the hypothesis that IFN-y induces increased expression of members of the TNF-receptor (TNFR) superfamily in cells nullizygous at the FAC locus, since several other members of this family are capable of inducing apoptosis either alone or in concert with each other. Using isogenic human EBV-transformed lymphoblast cell lines and murine c-kit+ bone marrow cells with inactivating mutations of the FAC locus, we quantified mRNA levels by RT-PCR 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-y-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 that inactivation of FAC does not augment expression of these proteins.

Original languageEnglish (US)
Pages (from-to)726
Number of pages1
JournalExperimental hematology
Volume26
Issue number8
StatePublished - 1998

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research

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