A novel mechanism of cooperation between c-Kit and erythropoietin receptor - Stem cell factor induces the expression of Stat5 and erythropoietin receptor, resulting in efficient proliferation and survival by erythropoietin

被引:62
作者
Kapur, R [1 ]
Zhang, L [1 ]
机构
[1] Indiana Univ, Sch Med, James Whitcomb Riley Hosp Children, Dept Pediat,Herman B Wells Ctr Pediat Res, Indianapolis, IN 46202 USA
关键词
D O I
10.1074/jbc.M007442200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Optimal production of red cells in vivo requires collaboration between c-Kit, erythropoietin receptor (Epo-R), and GATA-1. However, the mechanism(s) of collaboration remain unclear. Utilizing an embryonic stem cell-derived erythroid progenitor cell line from mice deficient in GATA-1, we have examined the role of c-Kit and Epo-R in erythroid cell proliferation, survival, and differentiation. In the absence of GATA-1, we demonstrate an essential role for c-Kit in survival and proliferation of erythroid progenitors via the regulation of Bcl-2 expression. In addition, we demonstrate that Epo-R and Stat5 are regulated by a second, novel mechanism. We demonstrate that c-Kit stimulation by stem cell factor is essential for the maintenance of Epo-R and Stat5 protein expression, which results in significantly enhanced Bcl-x(L) induction and survival of erythroid progenitors in response to Epo stimulation Restoration of GATA-1 function results in terminal erythroid maturation and up-regulation of Epo-R and Bcl-K, expression, leading also to significantly enhanced survival of terminally differentiating erythroid progenitors in the presence of only Epo, These results demonstrate that c-Kit and Epo-R have unique role(s) during distinct phases of erythroid maturation, and both stem cell factor and Epo contribute to the regulation of the Epo-R-Stat5-Bcl-x(L) pathway to ensure optimal survival, proliferation, and differentiation of erythroid progenitors.
引用
收藏
页码:1099 / 1106
页数:8
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