TRANSFORMING GROWTH-FACTOR-BETA-1 INHIBITS EXPRESSION OF THE GENE-PRODUCTS FOR STEEL FACTOR AND ITS RECEPTOR (C-KIT)
TRANSFORMING GROWTH-FACTOR-BETA-1 INHIBITS EXPRESSION OF THE GENE-PRODUCTS FOR STEEL FACTOR AND ITS RECEPTOR (C-KIT)
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DOI：
10.1182/blood.v85.7.1769.bloodjournal8571769
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发表时间：
1995-04-01
期刊：
影响因子：
20.3
通讯作者：
KEEBLE, WW
中科院分区：
文献类型：
--
作者：
HEINRICH, MC;DOOLEY, DC;KEEBLE, WW
转化生长因子β 1 （tgf - β 1）是骨髓基质细胞的产物，在造血微环境中抑制造血祖细胞的增殖和分化。钢铁因子（SF）也是骨髓基质细胞的产物，是体内重要的造血正调节因子。tgf - β 1已被证明可以抑制人和小鼠白血病细胞和小鼠骨髓单核细胞中SF受体（c-kit）的表达。我们推测tgf - β 1可能部分通过降低SF/c-kit相互作用来发挥其对造血的抑制作用。因此，我们验证了tgf - β 1抑制基质细胞SF表达和造血祖细胞c-kit表达的假设。我们测量了暴露于重组人tgf - β 1前后基质细胞SF蛋白的表达和造血祖细胞膜结合c-kit的表达。tgf - β 1对基质细胞SF蛋白表达和造血祖细胞c-kit蛋白表达均有50% ~ 80%的抑制作用。通过Northern blot和核糖核酸酶保护实验，我们确定tgf - β 1抑制基质细胞SF mRNA，但不改变SF转录物的稳定性。tgf - β 1也被发现抑制人白血病成髓细胞和正常lin（-）造血祖细胞中的c-kit mRNA。与其对SF mRNA的影响相反，tgf - β 1加速了c-kit mRNA的降解。我们得出结论，tgf - β 1通过抑制SF基因转录抑制基质细胞生成SF，并通过降低c-kit转录物的稳定性抑制造血祖细胞c-kit的表达。考虑到SF和c-kit在维持体内稳态造血中的重要性，igf - β 1对SF和c-kit基因表达的双重作用可能是tgf - β 1抑制体内造血的主要机制之一。(C) 1995年由美国血液病学会出版。
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 IGF-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. (C) 1995 by The American Society of Hematology.