Transforming growth factor beta 1 inhibits expression of the gene products for steel factor and its receptor (c-kit).
Transforming growth factor beta 1 (TGF-beta 1), 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-beta 1 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-beta 1 might exert its inhibitory effect on hematopoiesis in part by decreasing SF/c-kit interactions. Therefore, we tested the hypothesis that TGF-beta 1 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-beta 1. Both stromal cell expression of SF protein and hematopoietic progenitor cell expression of c-kit protein were inhibited 50% to 80% by TGF-beta 1. Using Northern blot and ribonuclease protection assays, we determined that TGF-beta 1 repressed stromal cell SF mRNA, but did not alter SF transcript stability. TGF-beta 1 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-beta 1 accelerated the degradation of c-kit mRNA. We conclude that TGF-beta 1 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-beta 1 on both SF and c-kit gene expression is likely to be one of the major mechanisms by which TGF-beta 1 inhibits hematopoiesis in vivo.
Heinrich
M C
MC
Department of Medicine, Oregon Health Sciences University, Portland, USA.
Dooley
D C
DC
Keeble
W W
WW
D000208:Acute Disease; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003238:Connective Tissue / Q000187:drug effects / Q000378:metabolism; D003864:Depression, Chemical; D005091:Exons; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D016298:Hematopoietic Cell Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D016184:Receptors, Colony-Stimulating Factor / Q000096:biosynthesis* / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D019089:Stem Cell Factor; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D016298:Hematopoietic Cell Growth Factors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016184:Receptors, Colony-Stimulating Factor; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D016212:Transforming Growth Factor beta; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases