title: Transforming growth factor-beta inhibits phosphorylation of the retinoblastoma susceptibility gene product in human monocytic leukemia cell line JOSK-I.
abstract: Proliferation of the human monocytic leukemia cell line JOSK-I is inhibited by transforming growth factor-beta (TGF-beta). Growth inhibition by TGF-beta was not due to either a toxic effect or to induction of differentiation. TGF-beta induced a cell cycle arrest at late G1 phase and was not found to be inhibitory to JOSK-I cells in S phase or G2/M. This G1 cell cycle arrest was associated with an accumulation of the unphosphorylated form of the retinoblastoma susceptibility gene product (Rb) in good correlation with inhibition of DNA synthesis. In contrast to the effects of TGF-beta, two other agents which induced a G1 arrest of JOSK-I cells had a different effect on Rb. Aphidicolin blocked cells at G1/S but could not reduce Rb phosphorylation as great as that seen with TGF-beta. 12-O-Tetradecanoylphorbol-13-acetate, an inducer of differentiation, did reduce Rb phosphorylation, but not until 72 h, when differentiation had already occurred. The identities of the Rb kinases are unknown, but recent evidence suggests that the cdc2 gene product could participate in Rb phosphorylation. Although cdc2 mRNA and total protein levels were not affected, TGF-beta inhibited the rate of translation and kinase activity of cdc2 in JOSK-I cells. These results suggest that growth inhibition of hematopoietic cells by TGF-beta is linked to suppression of Rb phosphorylation to retain Rb in an unphosphorylated, growth-inhibitory state. The suppression of Rb phosphorylation is suggested to be mediated through inhibition of cdc2 kinase activity by TGF-beta.
authors.affiliation: Division of Hemopoiesis, Institute of Hematology, Jichi Medical School, Tochigi, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Furukawa
authors.forename: S
authors.initials: S
authors.lastname: Uenoyama
authors.forename: M
authors.initials: M
authors.lastname: Ohta
authors.forename: A
authors.initials: A
authors.lastname: Tsunoda
authors.forename: J D
authors.initials: JD
authors.lastname: Griffin
authors.forename: M
authors.initials: M
authors.lastname: Saito
mesh_terms: D016590:Aphidicolin / Q000494:pharmacology; D015152:Blotting, Northern; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D004261:DNA Replication / Q000187:drug effects; D016161:Genes, Retinoblastoma / Q000187:drug effects*; D006684:HLA-DR Antigens / Q000096:biosynthesis; D006801:Humans; D007700:Kinetics; D007951:Leukemia, Myeloid; D010766:Phosphorylation; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D011990:Receptors, Transferrin / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013937:Thymidine Kinase / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D006684:HLA-DR Antigens; D012334:RNA, Neoplasm; D011990:Receptors, Transferrin; D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta; D016590:Aphidicolin; D013937:Thymidine Kinase; D013755:Tetradecanoylphorbol Acetate