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Inhibition of Transforming Growth Factor ß Signaling in MCF-7 Cells Results in Resistance to Tumor Necrosis Factor : A Role for Bcl-2¹

Departments of Medicine [S. W. T., K. D., D. C. P., B. A. A.] and Pharmacology [M. K. B., A. E.], Dartmouth Medical School, Hanover, New Hampshire 03755

Transforming growth factor ß (TGF-ß) is a multifunctional cytokine capable of regulating diverse cellular processes. In this study we investigated the effect of autocrine TGF-ß signaling on tumor necrosis factor (TNF) -induced cell death. We abrogated the TGF-ß autocrine loop by overexpression of a truncated TGF-ß type II receptor in MCF-7 breast carcinoma cells and found that this generated resistance to TNF--induced cytotoxicity. To elucidate the molecular basis of the influence of TGF-ß on TNF--induced cytotoxicity, we evaluated the expression levels or activities of proteins involved in TNF- signal transduction or the regulation of apoptosis in general in TGF-ß-responsive and TGF-ß-nonresponsive MCF-7 cells. We observed no significant difference in the expression of TNF- receptors or the TNF receptor-associated death domain protein. In addition, downstream activation of nuclear factor B by TNF- was not altered in cells that had lost TGF-ß responsiveness. Analysis of members of the Bcl-2 family of apoptosis-regulatory proteins revealed that Bcl-X_L and Bax expression levels were not changed by disruption of TGF-ß signaling. In contrast, the TGF-ß-nonresponsive cells expressed much higher levels of Bcl-2 protein and mRNA than did cells with an intact TGF-ß autocrine loop. Furthermore, restoration of a TGF-ß signal to MCF-7 cells that had spontaneously acquired resistance to TGF-ß caused a reduction in Bcl-2 protein expression. Taken together, our data indicate that loss of autocrine TGF-ß signaling results in enhanced resistance to TNF--mediated cell death and that this is likely to be mediated by derepression of Bcl-2 expression.

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