IKKγ protein is a target of BAG3 regulatory activity in human tumor growth
- 5 April 2010
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 107 (16), 7497-7502
- https://doi.org/10.1073/pnas.0907696107
Abstract
BAG3, a member of the BAG family of heat shock protein (HSP) 70 cochaperones, is expressed in response to stressful stimuli in a number of normal cell types and constitutively in a variety of tumors, including pancreas carcinomas, lymphocytic and myeloblastic leukemias, and thyroid carcinomas. Down-regulation of BAG3 results in cell death, but the underlying molecular mechanisms are still elusive. Here, we investigated the molecular mechanism of BAG3-dependent survival in human osteosarcoma (SAOS-2) and melanoma (M14) cells. We show that bag3 overexpression in tumors promotes survival through the NF-kappaB pathway. Indeed, we demonstrate that BAG3 alters the interaction between HSP70 and IKKgamma, increasing availability of IKKgamma and protecting it from proteasome-dependent degradation; this, in turn, results in increased NF-kappaB activity and survival. These results identify bag3 as a potential target for anticancer therapies in those tumors in which this gene is constitutively expressed. As a proof of principle, we show that treatment of a mouse xenograft tumor model with bag3siRNA-adenovirus that down-regulates bag3 results in reduced tumor growth and increased animal survival.This publication has 59 references indexed in Scilit:
- Inhibition of the JNK signalling pathway enhances proteasome inhibitor-induced apoptosis of kidney cancer cells by suppression of BAG3 expressionBritish Journal of Pharmacology, 2009
- HSF1-mediated BAG3 Expression Attenuates Apoptosis in 4-Hydroxynonenal-treated Colon Cancer Cells via Stabilization of Anti-apoptotic Bcl-2 ProteinsOnline Journal of Public Health Informatics, 2009
- Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3The EMBO Journal, 2009
- Altered gene expression in busulfan-resistant human myeloid leukemiaLeukemia Research, 2008
- Cells migrating to sites of tissue damage in response to the danger signal HMGB1 require NF-κB activationThe Journal of cell biology, 2007
- Heat Shock Factor 1 Is a Powerful Multifaceted Modifier of CarcinogenesisCell, 2007
- Evidence for BAG3 modulation of HIV‐1 gene transcriptionJournal of Cellular Physiology, 2006
- BAG3 Deficiency Results in Fulminant Myopathy and Early LethalityThe American Journal of Pathology, 2006
- Bis induces growth inhibition and differentiation of HL-60 cells via up-regulation of p27Experimental & Molecular Medicine, 2005
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001