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A TRAF2 binding independent region of TNFR2 is responsible for TRAF2 depletion and enhancement of cytotoxicity driven by TNFR1.
Oncotarget. 2014 Jan 15; 5(1):224-36.O

Abstract

Tumor Necrosis Factor (TNF) interacts with two receptors known as TNFR1 and TNFR2. TNFR1 activation may result in either cell proliferation or cell death. TNFR2 activates Nuclear Factor-kappaB (NF-kB) and c-Jun N-terminal kinase (JNK) which lead to transcriptional activation of genes related to cell proliferation and survival. This depends on the binding of TNF Receptor Associated Factor 2 (TRAF2) to the receptor. TNFR2 also induces TRAF2 degradation. In this work we have investigated the structural features of TNFR2 responsible for inducing TRAF2 degradation and have studied the biological consequences of this activity. We show that when TNFR1 and TNFR2 are co-expressed, TRAF2 depletion leads to an enhanced TNFR1 cytotoxicity which correlates with the inhibition of NF-kB. NF-kB activation and TRAF2 degradation depend of different regions of the receptor since TNFR2 mutants at amino acids 343-349 fail to induce TRAF2 degradation and have lost their ability to enhance TNFR1-mediated cell death but are still able to activate NF-kB. Moreover, whereas NF-kB activation requires TRAF2 binding to the receptor, TRAF2 degradation appears independent of TRAF2 binding. Thus, TNFR2 mutants unable to bind TRAF2 are still able to induce its degradation and to enhance TNFR1-mediated cytotoxicity. To test further this receptor crosstalk we have developed a system stably expressing in cells carrying only endogenous TNFR1 the chimeric receptor RANK-TNFR2, formed by the extracellular region of RANK (Receptor activator of NF-kB) and the intracellular region of TNFR2.This has made possible to study independently the signals triggered by TNFR1 and TNFR2. In these cells TNFR1 is selectively activated by soluble TNF (sTNF) while RANK-TNFR2 is selectively activated by RANKL. Treatment of these cells with sTNF and RANKL leads to an enhanced cytotoxicity.

Authors+Show Affiliations

Departamento de Bioquímica y Biología Molecular and Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

24318359

Citation

Cabal-Hierro, Lucía, et al. "A TRAF2 Binding Independent Region of TNFR2 Is Responsible for TRAF2 Depletion and Enhancement of Cytotoxicity Driven By TNFR1." Oncotarget, vol. 5, no. 1, 2014, pp. 224-36.
Cabal-Hierro L, Artime N, Iglesias J, et al. A TRAF2 binding independent region of TNFR2 is responsible for TRAF2 depletion and enhancement of cytotoxicity driven by TNFR1. Oncotarget. 2014;5(1):224-36.
Cabal-Hierro, L., Artime, N., Iglesias, J., Prado, M. A., Ugarte-Gil, L., Casado, P., Fernández-García, B., Darnay, B. G., & Lazo, P. S. (2014). A TRAF2 binding independent region of TNFR2 is responsible for TRAF2 depletion and enhancement of cytotoxicity driven by TNFR1. Oncotarget, 5(1), 224-36.
Cabal-Hierro L, et al. A TRAF2 Binding Independent Region of TNFR2 Is Responsible for TRAF2 Depletion and Enhancement of Cytotoxicity Driven By TNFR1. Oncotarget. 2014 Jan 15;5(1):224-36. PubMed PMID: 24318359.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A TRAF2 binding independent region of TNFR2 is responsible for TRAF2 depletion and enhancement of cytotoxicity driven by TNFR1. AU - Cabal-Hierro,Lucía, AU - Artime,Noelia, AU - Iglesias,Julián, AU - Prado,Miguel A, AU - Ugarte-Gil,Lorea, AU - Casado,Pedro, AU - Fernández-García,Belén, AU - Darnay,Bryant G, AU - Lazo,Pedro S, PY - 2013/12/10/entrez PY - 2013/12/10/pubmed PY - 2014/12/15/medline SP - 224 EP - 36 JF - Oncotarget JO - Oncotarget VL - 5 IS - 1 N2 - Tumor Necrosis Factor (TNF) interacts with two receptors known as TNFR1 and TNFR2. TNFR1 activation may result in either cell proliferation or cell death. TNFR2 activates Nuclear Factor-kappaB (NF-kB) and c-Jun N-terminal kinase (JNK) which lead to transcriptional activation of genes related to cell proliferation and survival. This depends on the binding of TNF Receptor Associated Factor 2 (TRAF2) to the receptor. TNFR2 also induces TRAF2 degradation. In this work we have investigated the structural features of TNFR2 responsible for inducing TRAF2 degradation and have studied the biological consequences of this activity. We show that when TNFR1 and TNFR2 are co-expressed, TRAF2 depletion leads to an enhanced TNFR1 cytotoxicity which correlates with the inhibition of NF-kB. NF-kB activation and TRAF2 degradation depend of different regions of the receptor since TNFR2 mutants at amino acids 343-349 fail to induce TRAF2 degradation and have lost their ability to enhance TNFR1-mediated cell death but are still able to activate NF-kB. Moreover, whereas NF-kB activation requires TRAF2 binding to the receptor, TRAF2 degradation appears independent of TRAF2 binding. Thus, TNFR2 mutants unable to bind TRAF2 are still able to induce its degradation and to enhance TNFR1-mediated cytotoxicity. To test further this receptor crosstalk we have developed a system stably expressing in cells carrying only endogenous TNFR1 the chimeric receptor RANK-TNFR2, formed by the extracellular region of RANK (Receptor activator of NF-kB) and the intracellular region of TNFR2.This has made possible to study independently the signals triggered by TNFR1 and TNFR2. In these cells TNFR1 is selectively activated by soluble TNF (sTNF) while RANK-TNFR2 is selectively activated by RANKL. Treatment of these cells with sTNF and RANKL leads to an enhanced cytotoxicity. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/24318359/A_TRAF2_binding_independent_region_of_TNFR2_is_responsible_for_TRAF2_depletion_and_enhancement_of_cytotoxicity_driven_by_TNFR1_ L2 - https://www.oncotarget.com/lookup/doi/10.18632/oncotarget.1492 DB - PRIME DP - Unbound Medicine ER -