Transforming growth factor β1 inhibits expression of the gene products for steel factor and its receptor (c-kit)

Michael C. Heinrich, Douglas C. Dooley, Winifred W. Keeble

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

Transforming growth factor β1 (TGF-β1), a product of marrow stromal cells, inhibits the proliferation and differentiation of hematopoietic progenitor cells within the hematopoietic microenvironment. Steel factor (SF), also a product of marrow stromal cells, is an essential positive regulator of hematopoiesis in vivo. TGF-β1 has been shown to repress human and murine leukemic cell and murine lin- bone marrow mononuclear cell expression of the receptor for SF (c-kit). We speculated that TGF-β1 might exert its inhibitory effect on hematopoiesis in part by decreasing SF/c-kit interactions. Therefore, we tested the hypothesis that TGF-β1 inhibits both stromal cell expression of SF and hematopoietic progenitor cell expression of c-kit. We measured stromal cell expression of SF protein and hematopoietic progenitor cell expression of membrane-bound c-kit before and after exposure to recombinant human TGF-β1. Both stromal cell expression of SF protein and hematopoietic progenitor cell expression of c-kit protein were inhibited 50% to 80% by TGF-β1. Using Northern blot and ribonuclease protection assays, we determined that TGF-β1 repressed stromal cell SF mRNA, but did not alter SF transcript stability. TGF-β1 was also found to repress c-kit mRNA in human leukemic myeloblasts as well as in normal lin- hematopoietic progenitor cells. In contrast with its effect on SF mRNA, TGF-β1 accelerated the degradation of c-kit mRNA. We conclude that TGF-β1 inhibits stromal cell production of SF by repression of SF gene transcription and represses hematopoietic progenitor cell expression of c-kit by decreasing the stability of c-kit transcripts. Taking into account the importance of SF and c-kit in maintaining steady-state hematopoiesis in vivo, the dual effect of TGF-β1 on both SF and c-kit gene expression is likely to be one of the major mechanisms by which TGF-β1 inhibits hematopoiesis in vivo.

Original languageEnglish (US)
Pages (from-to)1769-1780
Number of pages12
JournalBlood
Volume85
Issue number7
DOIs
StatePublished - Apr 1 1995
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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