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Inhibition of transforming growth factor beta signaling in MCF-7 cells results in resistance to tumor necrosis factor alpha: a role for Bcl-2.
Cell Growth Differ 2001; 12(2):109-17CG

Abstract

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

Authors+Show Affiliations

Department of Medicine, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11243465

Citation

Tobin, S W., et al. "Inhibition of Transforming Growth Factor Beta Signaling in MCF-7 Cells Results in Resistance to Tumor Necrosis Factor Alpha: a Role for Bcl-2." Cell Growth & Differentiation : the Molecular Biology Journal of the American Association for Cancer Research, vol. 12, no. 2, 2001, pp. 109-17.
Tobin SW, Brown MK, Douville K, et al. Inhibition of transforming growth factor beta signaling in MCF-7 cells results in resistance to tumor necrosis factor alpha: a role for Bcl-2. Cell Growth Differ. 2001;12(2):109-17.
Tobin, S. W., Brown, M. K., Douville, K., Payne, D. C., Eastman, A., & Arrick, B. A. (2001). Inhibition of transforming growth factor beta signaling in MCF-7 cells results in resistance to tumor necrosis factor alpha: a role for Bcl-2. Cell Growth & Differentiation : the Molecular Biology Journal of the American Association for Cancer Research, 12(2), pp. 109-17.
Tobin SW, et al. Inhibition of Transforming Growth Factor Beta Signaling in MCF-7 Cells Results in Resistance to Tumor Necrosis Factor Alpha: a Role for Bcl-2. Cell Growth Differ. 2001;12(2):109-17. PubMed PMID: 11243465.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of transforming growth factor beta signaling in MCF-7 cells results in resistance to tumor necrosis factor alpha: a role for Bcl-2. AU - Tobin,S W, AU - Brown,M K, AU - Douville,K, AU - Payne,D C, AU - Eastman,A, AU - Arrick,B A, PY - 2001/3/13/pubmed PY - 2001/5/26/medline PY - 2001/3/13/entrez SP - 109 EP - 17 JF - Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research JO - Cell Growth Differ. VL - 12 IS - 2 N2 - Transforming growth factor beta (TGF-beta) is a multifunctional cytokine capable of regulating diverse cellular processes. In this study we investigated the effect of autocrine TGF-beta signaling on tumor necrosis factor (TNF) alpha-induced cell death. We abrogated the TGF-beta autocrine loop by overexpression of a truncated TGF-beta type II receptor in MCF-7 breast carcinoma cells and found that this generated resistance to TNF-alpha-induced cytotoxicity. To elucidate the molecular basis of the influence of TGF-beta on TNF-alpha-induced cytotoxicity, we evaluated the expression levels or activities of proteins involved in TNF-alpha signal transduction or the regulation of apoptosis in general in TGF-beta-responsive and TGF-beta-nonresponsive MCF-7 cells. We observed no significant difference in the expression of TNF-alpha receptors or the TNF receptor-associated death domain protein. In addition, downstream activation of nuclear factor kappaB by TNF-alpha was not altered in cells that had lost TGF-beta 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-beta signaling. In contrast, the TGF-beta-nonresponsive cells expressed much higher levels of Bcl-2 protein and mRNA than did cells with an intact TGF-beta autocrine loop. Furthermore, restoration of a TGF-beta signal to MCF-7 cells that had spontaneously acquired resistance to TGF-beta caused a reduction in Bcl-2 protein expression. Taken together, our data indicate that loss of autocrine TGF-beta signaling results in enhanced resistance to TNF-alpha-mediated cell death and that this is likely to be mediated by derepression of Bcl-2 expression. SN - 1044-9523 UR - https://www.unboundmedicine.com/medline/citation/11243465/Inhibition_of_transforming_growth_factor_beta_signaling_in_MCF_7_cells_results_in_resistance_to_tumor_necrosis_factor_alpha:_a_role_for_Bcl_2_ L2 - http://cgd.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11243465 DB - PRIME DP - Unbound Medicine ER -