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 to 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 hematopoietic progenitor cells in p53-deficient mice to determine whether an inhibitory signal from TGF-beta 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-beta. Contrary to an earlier report, an erythroid and a granulocyte-macrophage progenitor, stimulated by IL-3, were not significantly inhibited, whereas TGF-beta 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-beta on the HPP-CFC was incompletely abolished. The response curve we obtained for graded doses of TGF-beta suggests that there is, at least, a subpopulation of HPP-CFC which 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 treated 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.
Sasaki
H
H
Department of Pediatrics, Yokohama City University School of Medicine, Japan.
Matsuda
M
M
Lu
Y
Y
Ikuta
K
K
Matsuyama
S
S
Hirabayashi
Y
Y
Mitsui
H
H
Matsumura
T
T
Muramatsu
M
M
Tsukada
T
T
Aizawa
S
S
Inoue
T
T
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D002455:Cell Division; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D016158:Genes, p53; D006131:Growth Inhibitors / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000145:classification / Q000166:cytology / Q000187:drug effects*; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000502:physiology
D006131:Growth Inhibitors; D007377:Interleukin-3; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53