Journal
ONCOGENE
Volume 32, Issue 38, Pages 4490-4499Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2012.480
Keywords
BAG-1; TGF-beta 1; colorectal cancer; adenoma; transcriptional repression
Funding
- Cancer Research UK programme grant
- Citrina Foundation
- John James Bristol Foundation
- CORE
- Cancer Research UK [11975] Funding Source: researchfish
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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 beta (TGF-beta 1) expression in colorectal tumour cells. Microarray analysis first highlighted the possibility that BAG-1 may regulate TGF-beta 1 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-beta 1 are inversely correlated in the normal colonic epithelium in vivo, consistent with a role for BAG-1-mediated repression of TGF-beta 1 production. In vitro studies showed that the change in TGF-beta 1 production following manipulation of BAG-1 is functionally relevant; through induction of anchorage-independent growth in TGF-beta 1-dependent normal rat kidney fibroblasts and regulation of SMAD2 phosphorylation in TGF-beta 1-sensitive adenoma cells. Taken together, this study identifies the anti-apoptotic protein BAG-1 as a suppressor of the inhibitory growth factor TGF-beta 1, 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-beta 1 has important biological implications, and highlights a new role for BAG-1 in colorectal tumorigenesis.
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