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Levels of phospho-Smad2/3 are sensors of the interplay between effects of TGF-beta and retinoic acid on monocytic and granulocytic differentiation of HL-60 cells

  1. Author:
    Cao, Z. H.
    Flanders, K. C.
    Bertolette, D.
    Lyakh, L. A.
    Wurthner, J. U.
    Parks, W. T.
    Letterio, J. J.
    Ruscetti, F. W.
    Roberts, A. B.

  2. Author Address

    NCI, Lab Cell Regulat & Carcinogenesis, Bldg 41,Rm C629,41 Lib Dr,MSC 5055, Bethesda, MD 20892 USA NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA NCI, Basic Res Lab, Frederick, MD 21701 USA Roberts AB NCI, Lab Cell Regulat & Carcinogenesis, Bldg 41,Rm C629,41 Lib Dr,MSC 5055, Bethesda, MD 20892 USA
    1. Year: 2003
  2. Journal: Blood
    1. 101
    2. 2
    3. Pages: 498-507
  4. Type of Article: Article
  1. Abstract:

    We have investigated the role of Smad family proteins, known to be important cytoplasmic mediators of signals from the transforming growth factor-beta (TGF-beta) receptor serine/threonine kinases, in TGF-beta-dependent differentiation of hematopoietic cells, using as a model the human promyelocytic leukemia cell line, HIL-60. TGF-beta-dependent differentiation of these cells to monocytes, but not retinoic acid-dependent differentiation to granulocytes, was accompanied by rapid phosphorylation and nuclear translocation of Smad2 and Smad3. Vitamin D-3 also induced phosphorylation of Smad2/3 and monocytic differentiation; however the effects were indirect, dependent on its ability to induce expression of TGF-beta1. Simultaneous treatment of these cells with TGF-beta1 and all- trans-retinoic acid (ATRA), which leads to almost equal numbers of granulocytes and monocytes, significantly reduced the level of phospho-Smad2/3 and its nuclear accumulation, compared with that in cells treated with TGF-beta1 alone. TGF-beta1 and ATRA activate P42/44 mitogen-activated protein (MAP) kinase with nearly identical kinetics, ruling out its involvement in these effects on Smad phosphorylation. Addition of the inhibitor-of- protein serine/threonine phosphatases, okadaic acid, blocks the ATRA-mediated reduction in TGF-beta-induced phospho-Smad2 and shifts the differentiation toward monocytic end points. In HL- 60R mutant cells, which harbor a defective retinoic acid receptor-alpha (RAR-alpha), ATRA is unable to reduce levels of TGF-beta-induced phospho-Smad2/3, coincident with its inability to differentiate these cells along granulocytic pathways. Together, these data suggest a new level of cross-talk between ATRA and TGF-beta, whereby a putative RAR-alpha-dependent phosphatase activity limits the levels of phospho-Smad2/3 induced by TGF-beta, ultimately reducing the levels of nuclear Smad complexes mediating the TGF-beta-dependent differentiation of the cells to monocytic end points. (C) 2003 by The American Society of Hematology.

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