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

Transforming growth factor-pi (TGF-beta1) can inhibit cell proliferation or induce apoptosis in multipotent hematopoietic cells. To study the mechanis ms of TGF-beta1 action on primitive hematopoietic cells, we used the interl eukin-3 (IL-3)-dependent, multipotent FDCP-Mix cell line. TGF-beta1-mediate d growth inhibition was observed in high concentrations of IL-3, while at l ower IL-3 concentrations TGF-beta1 induced apoptosis. The proapoptotic effe cts 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 t o 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-beta 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-beta1-induced apoptosis but was incapable of inhibiti ng TGF-beta1-mediated growth arrest. We conclude that TGF-beta1-induced cel l 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 mar row are discussed.