A fraction unresponsive to growth inhibition by TGF-β among the high-proliferative potential progenitor cells in bone marrow of p53-deficient mice

Abstract

Transforming growth factor-β (TGF- β) has been found to block the progression of the cell-cycle by up-regulating a Cdk inhibitor, p15, 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 erythroid 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-β 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.