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J. Biol. Chem., Vol. 275, Issue 50, 39137-39145, December 15, 2000

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Transforming Growth Factor-1 Induces Apoptosis Independently of p53 and Selectively Reduces Expression of Bcl-2 in Multipotent Hematopoietic Cells^*

Julia M. Francis^§, Clare M. Heyworth^§, Elaine Spooncer^¶, Andrew Pierce, T. Michael Dexter^§, and Anthony D. Whetton

From the  Leukaemia Research Fund Cellular Development Unit, ^¶ Department of Biomolecular Sciences, UMIST, Sackville St., Manchester, M60 1QD, United Kingdom and the ^§ Cancer Research Campaign, Department of Experimental Haematology, Paterson Institute for Cancer Research, Christie Hospital, NHS Trust, Manchester, M20 9BX, United Kingdom

Transforming growth factor-1 (TGF-1) can inhibit cell proliferation or induce apoptosis in multipotent hematopoietic cells. To study the mechanisms of TGF-1 action on primitive hematopoietic cells, we used the interleukin-3 (IL-3)-dependent, multipotent FDCP-Mix cell line. TGF-1-mediated growth inhibition was observed in high concentrations of IL-3, while at lower IL-3 concentrations TGF-1 induced apoptosis. The proapoptotic effects of TGF-1 occur via a p53-independent pathway, since p53^null FDCP-Mix demonstrated the same responses to TGF-1. 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-1 induced any change in Bcl-x_L protein levels or the proapoptotic proteins Bad or Bax. However, TGF-1 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-1-induced apoptosis but was incapable of inhibiting TGF-1-mediated growth arrest. We conclude that TGF-1-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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