Transforming growth factor-beta regulates c-kit message stability and cell-surface protein expression in hematopoietic progenitors.
Transforming growth factor-beta regulates c-kit message stability and cell-surface protein expression in hematopoietic progenitors.
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DOI：
10.1182/blood.v83.11.3138.bloodjournal83113138
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发表时间：
1994-06
期刊：
影响因子：
20.3
通讯作者：
C. Dubois;F. Ruscetti;J. Stankova;J. Keller
中科院分区：
文献类型：
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作者：
C. Dubois;F. Ruscetti;J. Stankova;J. Keller
细胞表面受体c-kit及其同源配体干细胞因子（SCF）或钢因子（SLF）对维持体外和体内造血功能都很重要。转化生长因子- β (tgf - β)已被证明是slf介导的小鼠Lin-Sca-1+祖细胞协同生长的有效抑制剂，以及更坚定的祖细胞。在本研究中，我们检测了tgf - β对c-kit mRNA和细胞表面表达的调节。在小鼠造血祖细胞中，骨髓细胞系FDC-P1和肥大细胞系MC-6以及祖细胞富集的骨髓细胞组成性表达功能性细胞表面c-kit。用tgf - β处理这些祖细胞系和原代祖细胞导致细胞表面c-kit表达下调。这种影响不是细胞周期状态的次要事件。tgf - β的抑制作用是剂量和时间依赖性的，在0.3至3 ng/mL tgf - β之间有50%的抑制作用，在30 ng/mL时最大抑制作用。使用FDC-P1细胞系，我们观察到tgf - β抑制细胞表面c-kit表达之前，tgf - β处理后2小时开始显著降低c-kit mRNA水平，并在6小时达到最大值。抑制稳态c-kit mRNA水平的部分原因是c-kit转录物的半衰期缩短（对照细胞为2至4小时，tgf - β处理细胞为0.5至1.5小时）。这些发现表明，tgf - β通过降低c-kit信息稳定性导致细胞表面表达降低来调节小鼠造血祖细胞对SLF的反应性。
The cell-surface receptor c-kit and its cognate ligand stem-cell factor (SCF) or steel factor (SLF) are important for the maintenance of hematopoiesis both in vitro and in vivo. Transforming growth factor-beta (TGF-beta) has been shown to be a potent inhibitor of SLF-mediated synergistic growth of murine Lin-Sca-1+ progenitor cells, as well as more committed progenitors. In the present study, we examined the regulation of c-kit mRNA and cell-surface expression by TGF-beta. Among the murine hematopoietic progenitor cells tested, the myeloid cell line FDC-P1 and the mast-cell line MC-6, as well as progenitor-enriched bone marrow cells, constitutively expressed functional cell-surface c-kit. Treatment of these progenitor cell lines and primary progenitor cells with TGF-beta resulted in downregulation of cell-surface c-kit expression. This effect was not a secondary event of cell-cycle status. TGF-beta inhibition was dose- and time-dependent, with 50% inhibition seen between 0.3 to 3 ng/mL TGF-beta and maximal inhibition at 30 ng/mL. Using the FDC-P1 cell line, we observed that the inhibition of cell-surface c-kit expression by TGF-beta is preceded by a marked reduction in c-kit mRNA levels starting 2 hours after TGF-beta treatment, and reaches a maximum by 6 hours. The inhibition in steady-state c-kit mRNA levels is explained, in part, by a decrease in the half-life of c-kit transcripts (2 to 4 hours for control cells v 0.5 to 1.5 hours for TGF-beta-treated cells). These findings suggest that TGF-beta regulates the responsiveness of murine hematopoietic progenitors to SLF through a decrease in c-kit message stability leading to decreased cell-surface expression.