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Transforming growth factor-beta 1 induces apoptosis independently of p53 and selectively reduces expression of Bcl-2 in multipotent hematopoietic cells.

Abstract

Transforming growth factor-beta1 (TGF-beta1) can inhibit cell proliferation or induce apoptosis in multipotent hematopoietic cells. To study the mechanisms of TGF-beta1 action on primitive hematopoietic cells, we used the interleukin-3 (IL-3)-dependent, multipotent FDCP-Mix cell line. TGF-beta1-mediated growth inhibition was observed in high concentrations of IL-3, while at lower IL-3 concentrations TGF-beta1 induced apoptosis. The proapoptotic effects of TGF-beta1 occur via a p53-independent pathway, since p53(null) FDCP-Mix demonstrated the same responses to TGF-beta1. IL-3 has been suggested to enhance survival via an increase in (antiapoptotic) Bcl-x(L) expression. In FDCP-Mix cells, neither IL-3 nor TGF-beta1 induced any change in Bcl-x(L) protein levels or the proapoptotic proteins Bad or Bax. However, TGF-beta1 had a major effect on Bcl-2 levels, reducing them in the presence of high and low concentrations of IL-3. Overexpression of Bcl-2 in FDCP-Mix cells rescued them from TGF-beta1-induced apoptosis but was incapable of inhibiting TGF-beta1-mediated growth arrest. We conclude that TGF-beta1-induced cell death is independent of p53 and inhibited by Bcl-2, with no effect on Bcl-x(L). The significance of these results for stem cell survival in bone marrow are discussed.

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  • Authors+Show Affiliations

    ,

    Leukaemia Research Fund Cellular Development Unit, Department of Biomolecular Sciences, UMIST, Sackville St., Manchester, M60 1QD, United Kingdom.

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    Source

    The Journal of biological chemistry 275:50 2000 Dec 15 pg 39137-45

    MeSH

    Animals
    Apoptosis
    Blotting, Western
    Carrier Proteins
    Cell Division
    Cell Line
    Cell Survival
    Dose-Response Relationship, Drug
    Electrophoresis, Polyacrylamide Gel
    Hematopoietic Stem Cells
    Humans
    Interleukin-3
    Mice
    Proto-Oncogene Proteins
    Proto-Oncogene Proteins c-bcl-2
    Time Factors
    Transforming Growth Factor beta
    Transforming Growth Factor beta1
    Tumor Suppressor Protein p53
    bcl-2-Associated X Protein
    bcl-Associated Death Protein
    bcl-X Protein

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    10993901

    Citation

    Francis, J M., et al. "Transforming Growth Factor-beta 1 Induces Apoptosis Independently of P53 and Selectively Reduces Expression of Bcl-2 in Multipotent Hematopoietic Cells." The Journal of Biological Chemistry, vol. 275, no. 50, 2000, pp. 39137-45.
    Francis JM, Heyworth CM, Spooncer E, et al. Transforming growth factor-beta 1 induces apoptosis independently of p53 and selectively reduces expression of Bcl-2 in multipotent hematopoietic cells. J Biol Chem. 2000;275(50):39137-45.
    Francis, J. M., Heyworth, C. M., Spooncer, E., Pierce, A., Dexter, T. M., & Whetton, A. D. (2000). Transforming growth factor-beta 1 induces apoptosis independently of p53 and selectively reduces expression of Bcl-2 in multipotent hematopoietic cells. The Journal of Biological Chemistry, 275(50), pp. 39137-45.
    Francis JM, et al. Transforming Growth Factor-beta 1 Induces Apoptosis Independently of P53 and Selectively Reduces Expression of Bcl-2 in Multipotent Hematopoietic Cells. J Biol Chem. 2000 Dec 15;275(50):39137-45. PubMed PMID: 10993901.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Transforming growth factor-beta 1 induces apoptosis independently of p53 and selectively reduces expression of Bcl-2 in multipotent hematopoietic cells. AU - Francis,J M, AU - Heyworth,C M, AU - Spooncer,E, AU - Pierce,A, AU - Dexter,T M, AU - Whetton,A D, PY - 2000/9/20/pubmed PY - 2001/3/3/medline PY - 2000/9/20/entrez SP - 39137 EP - 45 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 275 IS - 50 N2 - Transforming growth factor-beta1 (TGF-beta1) can inhibit cell proliferation or induce apoptosis in multipotent hematopoietic cells. To study the mechanisms of TGF-beta1 action on primitive hematopoietic cells, we used the interleukin-3 (IL-3)-dependent, multipotent FDCP-Mix cell line. TGF-beta1-mediated growth inhibition was observed in high concentrations of IL-3, while at lower IL-3 concentrations TGF-beta1 induced apoptosis. The proapoptotic effects of TGF-beta1 occur via a p53-independent pathway, since p53(null) FDCP-Mix demonstrated the same responses to TGF-beta1. IL-3 has been suggested to enhance survival via an increase in (antiapoptotic) Bcl-x(L) expression. In FDCP-Mix cells, neither IL-3 nor TGF-beta1 induced any change in Bcl-x(L) protein levels or the proapoptotic proteins Bad or Bax. However, TGF-beta1 had a major effect on Bcl-2 levels, reducing them in the presence of high and low concentrations of IL-3. Overexpression of Bcl-2 in FDCP-Mix cells rescued them from TGF-beta1-induced apoptosis but was incapable of inhibiting TGF-beta1-mediated growth arrest. We conclude that TGF-beta1-induced cell death is independent of p53 and inhibited by Bcl-2, with no effect on Bcl-x(L). The significance of these results for stem cell survival in bone marrow are discussed. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/10993901/Transforming_growth_factor_beta_1_induces_apoptosis_independently_of_p53_and_selectively_reduces_expression_of_Bcl_2_in_multipotent_hematopoietic_cells_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=10993901 DB - PRIME DP - Unbound Medicine ER -