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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 Feb; 12(2):109-17.CG

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.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

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), 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 -