Skip to main content

Research Repository

Advanced Search

BAG-1 suppresses expression of the key regulatory cytokine transforming growth factor β (TGF-β1) in colorectal tumour cells

Skeen, V. R.; Collard, T. J.; Southern, S. L.; Hague, A.; Townsend, P. A.; Paraskeva, C.; Williams, A. C.; Skeen, Victoria R; Collard, Tracey J; Southern, Samantha L; Hague, Angela; Townsend, Paul; Paraskeva, Chris; Williams, Ann C; Greenhough, A.

Authors

V. R. Skeen

T. J. Collard

S. L. Southern

A. Hague

P. A. Townsend

C. Paraskeva

A. C. Williams

Victoria R Skeen

Tracey J Collard

Samantha L Southern

Angela Hague

Paul Townsend

Chris Paraskeva

Ann C Williams



Abstract

As colorectal cancer remains the second highest cause of cancer-related deaths in much of the industrialised world, identifying novel strategies to prevent colorectal tumour development remains an important challenge. BAG-1 is a multi-functional protein, the expression of which is up-regulated at relatively early stages in colorectal tumorigenesis. Importantly, BAG-1 is thought to enhance colorectal tumour progression through promoting tumour cell survival. Here, we report for the first time a novel role for BAG-1, establishing it as a suppressor of transforming growth factor β (TGF-β1) expression in colorectal tumour cells. Microarray analysis first highlighted the possibility that BAG-1 may regulate TGF-β1 expression, a key cytokine in normal colonic tissue homoeostasis. Q-RT-PCR and ELISA demonstrated TGFB1 mRNA and protein expression to be significantly increased when BAG1 levels were reduced by small interfering RNA; additionally, induction of BAG-1L caused suppression of TGFB1 mRNA in colorectal tumour cells. Using reporter and chromatin immunoprecipitation assays, a direct association of BAG-1 with the TGFB1 gene regulatory region was identified. Immunohistochemistry and Weiser fraction data indicated that the levels of BAG-1 and TGF-β1 are inversely correlated in the normal colonic epithelium in vivo, consistent with a role for BAG-1-mediated repression of TGF-β1 production. In vitro studies showed that the change in TGF-β1 production following manipulation of BAG-1 is functionally relevant; through induction of anchorage-independent growth in TGF-β1-dependent normal rat kidney fibroblasts and regulation of SMAD2 phosphorylation in TGF-β1-sensitive adenoma cells. Taken together, this study identifies the anti-apoptotic protein BAG-1 as a suppressor of the inhibitory growth factor TGF-β1, suggesting that high expression of BAG-1 can impact on a number of the hallmarks of cancer, of potential importance in promoting the early stages of colorectal tumorigenesis. Establishing BAG-1 as a repressor of TGF-β1 has important biological implications, and highlights a new role for BAG-1 in colorectal tumorigenesis. © 2013 Macmillan Publishers Limited.

Journal Article Type Article
Acceptance Date Sep 2, 2012
Online Publication Date Oct 29, 2012
Publication Date Sep 19, 2013
Journal Oncogene
Print ISSN 0950-9232
Electronic ISSN 1476-5594
Publisher Springer Nature [academic journals on nature.com]
Peer Reviewed Peer Reviewed
Volume 32
Issue 38
Pages 4490-4499
DOI https://doi.org/10.1038/onc.2012.480
Public URL https://uwe-repository.worktribe.com/output/927685
Publisher URL https://doi.org/10.1038/onc.2012.480