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Genetic deletion of glycogen synthase kinase-3beta abrogates activation of IkappaBalpha kinase, JNK, Akt, and p44/p42 MAPK but potentiates apoptosis induced by tumor necrosis factor.
J Biol Chem. 2004 Sep 17; 279(38):39541-54.JB

Abstract

Glycogen synthase kinase (GSK)-3beta is a constitutively active, proline-directed serine/threonine kinase that controls growth modulation and tumorigenesis through multiple intracellular signaling pathways. How GSK-3beta regulates signaling pathways induced by cytokines such as tumor necrosis factor (TNF) is poorly understood. In this study, we used fibroblasts derived from GSK-3beta gene-deleted mice to understand the role of this kinase in TNF signaling. TNF induced NF-kappaB activation as measured by DNA binding in wild-type mouse embryonic fibroblasts, but deletion of GSK-3beta abolished this activation. This inhibition was due to suppression of IkappaBalpha kinase activation and IkappaBalpha phosphorylation, ubiquitination, and degradation. TNF-induced NF-kappaB reporter gene transcription was also suppressed in GSK-3beta gene-deleted cells. NF-kappaB activation induced by lipopolysaccharide, interleukin-1beta, or cigarette smoke condensate was completely suppressed in GSK-3beta(-/-) cells. Deletion of GSK-3beta also abolished TNF-induced c-Jun N-terminal kinase and p44/p42 mitogen-activated kinase activation. Most surprisingly, TNF-induced Akt activation also required the presence of GSK-3beta. TNF induced expression of the NF-kappaB-regulated gene products cyclin D1, COX-2, MMP-9, survivin, IAP 1, IAP 2, Bcl-x(L), Bfl-1/A1, TRAF1, and FLIP in wild-type mouse embryonic fibroblasts but not in GSK-3beta(-/-) cells, and this correlated with potentiation of TNF-induced apoptosis as indicated by cell viability, annexin V staining, and caspase activation. Overall, our results indicate that GSK-3beta plays a critical role in TNF signaling and in the signaling of other inflammatory stimuli and that its suppression can be exploited as a potential target to inhibit angiogenesis, proliferation, and survival of tumor cells.

Authors+Show Affiliations

Cytokine Research Laboratory, Department of Bioimmunotherapy, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

15252041

Citation

Takada, Yasunari, et al. "Genetic Deletion of Glycogen Synthase Kinase-3beta Abrogates Activation of IkappaBalpha Kinase, JNK, Akt, and P44/p42 MAPK but Potentiates Apoptosis Induced By Tumor Necrosis Factor." The Journal of Biological Chemistry, vol. 279, no. 38, 2004, pp. 39541-54.
Takada Y, Fang X, Jamaluddin MS, et al. Genetic deletion of glycogen synthase kinase-3beta abrogates activation of IkappaBalpha kinase, JNK, Akt, and p44/p42 MAPK but potentiates apoptosis induced by tumor necrosis factor. J Biol Chem. 2004;279(38):39541-54.
Takada, Y., Fang, X., Jamaluddin, M. S., Boyd, D. D., & Aggarwal, B. B. (2004). Genetic deletion of glycogen synthase kinase-3beta abrogates activation of IkappaBalpha kinase, JNK, Akt, and p44/p42 MAPK but potentiates apoptosis induced by tumor necrosis factor. The Journal of Biological Chemistry, 279(38), 39541-54.
Takada Y, et al. Genetic Deletion of Glycogen Synthase Kinase-3beta Abrogates Activation of IkappaBalpha Kinase, JNK, Akt, and P44/p42 MAPK but Potentiates Apoptosis Induced By Tumor Necrosis Factor. J Biol Chem. 2004 Sep 17;279(38):39541-54. PubMed PMID: 15252041.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genetic deletion of glycogen synthase kinase-3beta abrogates activation of IkappaBalpha kinase, JNK, Akt, and p44/p42 MAPK but potentiates apoptosis induced by tumor necrosis factor. AU - Takada,Yasunari, AU - Fang,Xianjun, AU - Jamaluddin,Md Saha, AU - Boyd,Douglas D, AU - Aggarwal,Bharat B, Y1 - 2004/07/13/ PY - 2004/7/15/pubmed PY - 2004/10/27/medline PY - 2004/7/15/entrez SP - 39541 EP - 54 JF - The Journal of biological chemistry JO - J Biol Chem VL - 279 IS - 38 N2 - Glycogen synthase kinase (GSK)-3beta is a constitutively active, proline-directed serine/threonine kinase that controls growth modulation and tumorigenesis through multiple intracellular signaling pathways. How GSK-3beta regulates signaling pathways induced by cytokines such as tumor necrosis factor (TNF) is poorly understood. In this study, we used fibroblasts derived from GSK-3beta gene-deleted mice to understand the role of this kinase in TNF signaling. TNF induced NF-kappaB activation as measured by DNA binding in wild-type mouse embryonic fibroblasts, but deletion of GSK-3beta abolished this activation. This inhibition was due to suppression of IkappaBalpha kinase activation and IkappaBalpha phosphorylation, ubiquitination, and degradation. TNF-induced NF-kappaB reporter gene transcription was also suppressed in GSK-3beta gene-deleted cells. NF-kappaB activation induced by lipopolysaccharide, interleukin-1beta, or cigarette smoke condensate was completely suppressed in GSK-3beta(-/-) cells. Deletion of GSK-3beta also abolished TNF-induced c-Jun N-terminal kinase and p44/p42 mitogen-activated kinase activation. Most surprisingly, TNF-induced Akt activation also required the presence of GSK-3beta. TNF induced expression of the NF-kappaB-regulated gene products cyclin D1, COX-2, MMP-9, survivin, IAP 1, IAP 2, Bcl-x(L), Bfl-1/A1, TRAF1, and FLIP in wild-type mouse embryonic fibroblasts but not in GSK-3beta(-/-) cells, and this correlated with potentiation of TNF-induced apoptosis as indicated by cell viability, annexin V staining, and caspase activation. Overall, our results indicate that GSK-3beta plays a critical role in TNF signaling and in the signaling of other inflammatory stimuli and that its suppression can be exploited as a potential target to inhibit angiogenesis, proliferation, and survival of tumor cells. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/15252041/Genetic_deletion_of_glycogen_synthase_kinase_3beta_abrogates_activation_of_IkappaBalpha_kinase_JNK_Akt_and_p44/p42_MAPK_but_potentiates_apoptosis_induced_by_tumor_necrosis_factor_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)72756-0 DB - PRIME DP - Unbound Medicine ER -