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Prepublished online as a Blood First Edition Paper on September 12, 2002; DOI 10.1182/blood-2002-05-1549. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-05-1549v1 101/2/498    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Cao, Z. Articles by Roberts, A. B. Search for Related Content PubMed PubMed Citation Articles by Cao, Z. Articles by Roberts, A. B. Related Collections Signal Transduction Hematopoiesis and Stem Cells Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 January 2003, Vol. 101, No. 2, pp. 498-507 HEMATOPOIESIS Levels of phospho-Smad2/3 are sensors of the interplay between effects of TGF- and retinoic acid on monocytic and granulocytic differentiation of HL-60 cells Zhouhong Cao, Kathleen C. Flanders, Daniel Bertolette, Lyudmila A. Lyakh, Jens U. Wurthner, W. Tony Parks, John J. Letterio, Francis W. Ruscetti, and Anita B. Roberts From the Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, MD, and the Basic Research Laboratory, National Cancer Institute (NCI)-Frederick, Frederick, MD. We have investigated the role of Smad family proteins, known to be important cytoplasmic mediators of signals from the transforming growth factor- (TGF-) receptor serine/threonine kinases, in TGF--dependent differentiation of hematopoietic cells, using as a model the human promyelocytic leukemia cell line, HL-60. TGF--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 D3 also induced phosphorylation of Smad2/3 and monocytic differentiation; however the effects were indirect, dependent on its ability to induce expression of TGF-1. Simultaneous treatment of these cells with TGF-1 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-1 alone. TGF-1 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--induced phospho-Smad2 and shifts the differentiation toward monocytic end points. In HL-60R mutant cells, which harbor a defective retinoic acid receptor- (RAR-), ATRA is unable to reduce levels of TGF--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-, whereby a putative RAR--dependent phosphatase activity limits the levels of phospho-Smad2/3 induced by TGF-, ultimately reducing the levels of nuclear Smad complexes mediating the TGF--dependent differentiation of the cells to monocytic end points. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Kawajiri, M. Yashiro, O. Shinto, K. Nakamura, M. Tendo, S. Takemura, M. Node, Y. Hamashima, T. Kajimoto, T. Sawada, et al. A Novel Transforming Growth Factor {beta} Receptor Kinase Inhibitor, A-77, Prevents the Peritoneal Dissemination of Scirrhous Gastric Carcinoma Clin. Cancer Res., May 1, 2008; 14(9): 2850 - 2860. [Abstract] [Full Text] [PDF] Y. Ji, H. J. Lee, C. Goodman, M. Uskokovic, K. Liby, M. Sporn, and N. 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