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

Michael Heinrich, D. C. Dooley, W. W. Keeble

Research output: Contribution to journalArticle

67 Citations (Scopus)

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
StatePublished - 1995
Externally publishedYes

Fingerprint

Proto-Oncogene Proteins c-kit
Stem Cell Factor
Transforming Growth Factors
Genes
Gene Expression
Stromal Cells
Hematopoietic Stem Cells
Hematopoiesis
Messenger RNA
Bone Marrow
Granulocyte Precursor Cells
Transcription
Ribonucleases
Gene expression
Bone Marrow Cells
Northern Blotting

ASJC Scopus subject areas

  • Hematology

Cite this

Transforming growth factor β1 inhibits expression of the gene products for steel factor and its receptor (c-kit). / Heinrich, Michael; Dooley, D. C.; Keeble, W. W.

In: Blood, Vol. 85, No. 7, 1995, p. 1769-1780.

Research output: Contribution to journalArticle

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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.",
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