Transforming growth factor beta inhibits growth of more differentiated myeloid leukemia cells and retinoblastoma protein phosphorylation at serine 795.
Transforming growth factor beta (TGF-beta) has been shown to be a specific inhibitor of early human myeloid progenitors. We show here that TGF-beta1 potentially inhibited not only the growth of primitive but also more mature myeloid leukemic cells. Surprisingly, those apparently more mature progenitor cells, such as MV4-11 and Mo7e cells, are very sensitive to the action of TGF-beta. The addition of TGF-beta1 to liquid cultures of these cells significantly inhibited their proliferation, with as much as 72% inhibition of growth of MV4-11 cells. The suppressive effect by TGF-beta1 was not reversed or prevented by granulocyte-macrophage colony-stimulating factor or interleukin 3 used to promote cell growth in TF-1a and MV4-11 cells. TGF-beta1 completely abolished the clonal growth of MV4-11 cells in soft agar and inhibited Mo7e, KG-1, K562, TF-1, and TF-1a colony growth by 99%, 90%, 63%, 53%, and 43%, respectively. The cells treated with TGF-beta1 showed progressive accumulation in the G1 phase of cell cycle. Maximal G1 arrest (93%) was observed in MV4-11 cells. Using anti-retinoblastoma protein (pRb) and anti-specific phosphorylated-pRb antibodies, we demonstrated that TGF-beta1 greatly inhibited pRb phosphorylation at serine 795 in MV4-11 and Mo7e cells. Taken together, our data suggest that the sensitivity of myeloid leukemic progenitor cells to growth inhibition by TGF-beta may not be inversely correlated with their maturation stage, and the inhibition of the cells appeared to be linked to the suppression of pRb phosphorylation at serine 795.
Hu
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Department of Internal Medicine, University of South Florida, and H. Lee Moffitt Cancer Center, and Research Institute, Tampa 33612, USA. hu@moffitt.usf.edu
Moscinski
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LC
Zuckerman
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D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects; D012694:Serine / Q000378:metabolism*; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta; D012694:Serine; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases