A FRACTION UNRESPONSIVE TO GROWTH-INHIBITION BY TGF-BETA AMONG THE HIGH-PROLIFERATIVE POTENTIAL PROGENITOR CELLS IN BONE-MARROW OF P53-DEFICIENT MICE

Transforming growth factor-beta (TGF-beta) 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 t o activate transcriptionally the gene for another Cdk inhibitor, p21. The regulatory effects of TGF-beta on hematopoietic tissues is poorly understood. Hence, we investigated the effect of TGF-beta on hematopoi etic progenitor cells in p53-deficient mice to determine whether an in hibitory signal from TGF-beta is linked to p53 in hematopoietic regula tion. We found that the proliferation of megakaryocyte-progenitors (CF U-Mk) in our wild-type mice was markedly inhibited by TGF-beta. Contra ry to an earlier report, an erythroid and a granulocyte-macrophage pro genitor, stimulated by IL-3, were not significantly inhibited, whereas TGF-beta also completely inhibited the growth of high-proliferative p otential progenitor cells (HPP-CFC) in the marrow of mice with 5-fluor ouracil (5FU), as reported. It is interesting that in the p53-deficien t mice, the inhibitory action of TGF-beta on the HPP-CFC was incomplet ely abolished. The response curve we obtained for graded doses of TGF- beta suggests that there is, at least, a subpopulation of HPP-CFC whic h is less sensitive to the regulation by TGF-beta. In contrast to HPP- CFC, the CFU-Mk, which TGF-beta inhibited only in wild-type mice not t reated with 5FU, remained inhibited in the p53-deficient strain. Thus, HPP-CFC might be regulated by TGF-beta through their signal pathways which are linked to p53.