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BAG-1 prevents stress-induced long-term growth inhibition in breast cancer cells via a chaperone-dependent pathway

BAG-1 prevents stress-induced long-term growth inhibition in breast cancer cells via a chaperone-dependent pathway
BAG-1 prevents stress-induced long-term growth inhibition in breast cancer cells via a chaperone-dependent pathway
BAG-1 is a multifunctional protein that interacts with a wide range of cellular targets. There is accumulating evidence that overexpression of BAG-1 may play an important role in breast cancer; however, the functional consequences of BAG-1 expression and its mechanism of action in breast cancer cells have not been studied in detail. Here we demonstrate that BAG-1 overexpression completely protected breast cancer cells from apoptosis and long-term growth inhibition induced by heat shock and also partially protected cells from other stresses, including hypoxia, radiation, and chemotoxic drugs. BAG-1 exists as three protein isoforms, and all isoforms prevented stress-induced growth inhibition.

This required a conserved lysine in the BAG-1S ubiquitin-like domain thought to be important for proteasome binding and COOH-terminal amino acids required for interaction with the chaperone molecules, Hsc70 and Hsp70. Although expression of BAG-1 was unaltered by heat shock, endogenous and overexpressed BAG-1S relocalized from the cytoplasm to the nucleus after heat shock. The endogenous BAG-1S·Hsc70/Hsp70 complex dissociated after heat shock but was maintained at a detectable level in cells overexpressing BAG-1S. BAG-1-mediated resistance to stress-induced growth inhibition is likely to have a major impact on the development and response to therapy of breast cancer. Targeting the interaction of BAG-1 with chaperones is an attractive strategy to counter the biological effects of BAG-1.
0008-5472
4150-4157
Townsend, Paul A.
a2680443-664e-46d0-b4dd-97456ba810db
Cutress, Ramsey I.
68ae4f86-e8cf-411f-a335-cdba51797406
Sharp, Adam
f26a1894-b10f-4864-a314-750628d6c0cc
Brimmell, Matthew
4bb675a5-c3f0-4ddb-ae49-d39257ba79e1
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Townsend, Paul A.
a2680443-664e-46d0-b4dd-97456ba810db
Cutress, Ramsey I.
68ae4f86-e8cf-411f-a335-cdba51797406
Sharp, Adam
f26a1894-b10f-4864-a314-750628d6c0cc
Brimmell, Matthew
4bb675a5-c3f0-4ddb-ae49-d39257ba79e1
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394

Townsend, Paul A., Cutress, Ramsey I., Sharp, Adam, Brimmell, Matthew and Packham, Graham (2003) BAG-1 prevents stress-induced long-term growth inhibition in breast cancer cells via a chaperone-dependent pathway. Cancer Research, 63 (14), 4150-4157. (PMID:12874020)

Record type: Article

Abstract

BAG-1 is a multifunctional protein that interacts with a wide range of cellular targets. There is accumulating evidence that overexpression of BAG-1 may play an important role in breast cancer; however, the functional consequences of BAG-1 expression and its mechanism of action in breast cancer cells have not been studied in detail. Here we demonstrate that BAG-1 overexpression completely protected breast cancer cells from apoptosis and long-term growth inhibition induced by heat shock and also partially protected cells from other stresses, including hypoxia, radiation, and chemotoxic drugs. BAG-1 exists as three protein isoforms, and all isoforms prevented stress-induced growth inhibition.

This required a conserved lysine in the BAG-1S ubiquitin-like domain thought to be important for proteasome binding and COOH-terminal amino acids required for interaction with the chaperone molecules, Hsc70 and Hsp70. Although expression of BAG-1 was unaltered by heat shock, endogenous and overexpressed BAG-1S relocalized from the cytoplasm to the nucleus after heat shock. The endogenous BAG-1S·Hsc70/Hsp70 complex dissociated after heat shock but was maintained at a detectable level in cells overexpressing BAG-1S. BAG-1-mediated resistance to stress-induced growth inhibition is likely to have a major impact on the development and response to therapy of breast cancer. Targeting the interaction of BAG-1 with chaperones is an attractive strategy to counter the biological effects of BAG-1.

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Published date: 15 July 2003

Identifiers

Local EPrints ID: 26642
URI: http://eprints.soton.ac.uk/id/eprint/26642
ISSN: 0008-5472
PURE UUID: a59d7ffe-eaa5-487d-ba61-2a8349472fc7
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691

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Date deposited: 24 Apr 2006
Last modified: 16 Mar 2024 03:14

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Contributors

Author: Paul A. Townsend
Author: Adam Sharp
Author: Matthew Brimmell
Author: Graham Packham ORCID iD

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