Signal transduction mediated by hematopoietic factors and TGF-β in p53-deficient mice

我们研究了造血因子和转化生长因子-p （TGF-β）对p53缺陷小鼠造血进程的影响，以阐明p53是否在TGF-p诱导的造血系统生长抑制中发挥作用。已发现TGF-p仅在上皮细胞中通过上调Cdk抑制剂p15来阻断细胞周期的进展；另一方面，野生型p53被证明可以激活另一种Cdk抑制剂p21的转录基因。TGF-β对造血组织的调节作用尚不清楚。因此，我们研究了TGF-β对p53缺陷小鼠造血祖细胞的影响，以确定TGF-β的抑制信号是否与p53的造血调节有关。我们发现TGF-β显著抑制野生型小鼠巨核细胞祖细胞（CFU-Mk）的增殖。与先前的报道相反，IL-3刺激的elytroid和粒细胞-巨噬细胞祖细胞未被显著抑制，而TGF-β也完全抑制了5-氟尿嘧啶（5FU）小鼠骨髓中高增殖潜能祖细胞（HPP-CFC）的生长。有趣的是，在p53缺失小鼠中，TGF- p对HPP-CFC的抑制作用并未完全消除。我们获得的分级剂量TGF-β的响应曲线表明，至少存在一个对TGF-β调控不太敏感的HPP-CFC亚群。与HPP-CFC相比，TGF-β仅在未接受5FU处理的野生型小鼠中抑制CFU-Mk，在p53缺失菌株中仍被抑制。因此，HPP-CFC可能通过与p53相关的信号通路受到TGF-β的调控。

We investigated the effect of hematopoietic factors and transforming growth factor-P (TGF-β)on hematopoietic progressions in p53-deficient mice to clarify whether p53 plays a role in TGF-p-induced growth inhibition in the hematopoietic system. TGF-p has been found to block the progression of the cell-cycle by up-regulating a Cdk inhibitor, p 15, only in epithelial cells ; on the other hand, wild-type p53 was shown to activate transcriptionally the gene for another Cdk inhibitor, p21. The regulatory effects of TGF-β on hematopoietic tissues is poorly understood. Hence, we investigated the effect of TGF-β on hematopoietic progenitor cells in p53-deficient mice to determine whether an inhibitory signal from TGF-β is linked to p53 in hematopoietic regulation. We found that the proliferation of megakaryocyte-progenitors (CFU-Mk) in our wild-type mice was markedly inhibited by TGF-β. Contrary to an earlier report an elytroid and a granulocyte-macrophage progenitor, stimulated by IL-3, were not significantly inhibited, whereas TGF-β also completely inhibited the growth of high-proliferative potential progenitor cells (HPP-CFC) in the marrow of mice with 5-fluorouracil (5FU), as reported. It is interesting that in the p53-deficient mice, the inhibitory action of TGF- p on the HPP-CFC was incompletely abolished. The response curve we obtained for graded doses of TGF-β suggests that there is, at least, a subpopulation of HPP-CFC which is less sensitive to the regulation by TGF-β. In contrast to HPP-CFC, the CFU-Mk, which TGF-β inhibited only in wild-type mice not treated with 5FU, remained inhibited in the p53-deficient strain. Thus, HPP-CFC might be regulated by TGF-β through their signal pathways which are linked to p53.