The BAG-1 cochaperone is a negative regulator of p73-dependent transcription

Xh, Wang; O’Connor, Daniel; Brimmell, Matthew; Packham, Graham

doi:10.1038/sj.bjc.6604985

Cited by 10 publications

(9 citation statements)

References 75 publications

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“…Importantly, the nuclear isoform of BAG-1 (BAG-1L) has been implicated in the control of transcription (reviewed in [ 16 ]). This may occur through direct interaction of BAG-1 with DNA [ 17 , 18 ], or through interaction with DNA-binding proteins such as nuclear hormone receptors [ 19 , 20 ], the retinoblastoma protein [ 13 ] or p73 [ 21 ]. More recently we have shown that, through direct interaction with homodimeric p50 NF-κB complexes, BAG-1 can regulate NF-κB dependent transcription at a sub-set of NF-κB target genes including the epidermal growth factor receptor ( EGFR ) and COX-2 ( PTGS2 ) [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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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-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 homeostasis. Q-RT-PCR and ELISA demonstrated TGFB1 mRNA and protein expression to be significantly increased when BAG1 levels were reduced by siRNA; additionally, induction of BAG-1L caused suppression of TGFB1 mRNA in colorectal tumour cells. Using reporter and ChIP assays, a direct association of BAG-1 with the TGFB1 gene regulatory region was identified. Immunohistochemistry and Weiser fraction data indicated 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 NRK 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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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“…However, this may well be a cell type-and stimulus-specific effect, as RAF-1 is known to elicit prosurvival signals through ERK-mediated phosphorylation of pro-and anti-apoptotic effectors such as BAD, BIM and BCL-2 (Kolch, 2000). Recently, Wang et al demonstrated BAG-1's ability to interact with and inhibit the transactivating function of p73, suggesting that this may contribute to BAG-1-mediated survival given p73's known role as a regulator of stress-induced apoptosis (Wang et al, 2009). Thus, BAG-1's prosurvival effects are likely to be mediated through multiple pathways depending on the cellular context and reflecting its numerous and varied binding partners.…”

Section: Introductionmentioning

confidence: 99%

BAG-1 overexpression attenuates luminal apoptosis in MCF-10A mammary epithelial cells through enhanced RAF-1 activation

2009

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Although the multi-functional, prosurvival protein, Bcl-2-associated anthanogene 1 (BAG-1) is frequently overexpressed in breast cancers, its role in the development or maintenance of the malignant state remains unclear. Here, we have used the established MCF-10A 3-dimensional (3D) model of mammary morphogenesis as a biologically relevant system to determine how BAG-1 expression may influence the development of breast cancer. When cultured in 3D, MCF-10A cells undergo a highly regulated morphogenic program leading to the development of polarized acinar structures containing a central, hollow lumen formed, in part, through the induction of BIM-dependent apoptosis. BAG-1 overexpression resulted in an attenuation of this normal apoptotic program characterized by a significantly increased number of acini with filled lumens-a phenotype commonly observed in ductal carcinoma in situ. BAG-1's effects were associated with an activation of RAF-1-a known binding partner of BAG-1, enhanced signaling through the MAP kinase pathway and a decrease in BIM expression. Reversal of the BAG-1-associated survival phenotype by the mitogen-activated kinase/ERK kinase inhibitor, U0126, implicates the RAF-1-extracellular signal-regulated kinase signaling pathway as a major mediator of BAG-1's effects in this model. As BAG-1 expression is often elevated in preinvasive breast cancers, these findings support a possible role for BAG-1 as an early contributor to the malignant process in the breast.

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“…Although it was initially identified as a Bcl-2 binding protein to suppress apoptosis [7], Bag-1 has been known to interact with and regulate the activity of other proteins. For example, Bag-1 interacts with and inhibits the function of the tumor suppressor p73 [8]. Furthermore, the medium isoform, Bag-1M is increased in the hippocampus of Alzheimer's disease patients and binds to Tau protein and amyloid precursor protein (APP), and overexpressed Bag-1M induces increased level of Tau and APP that are related with the pathology and treatment of Alzheimer disease [9,10].…”

Section: Introductionmentioning

confidence: 99%

Bag‐1M inhibits the transactivation of the glucocorticoid receptor via recruitment of corepressors

Wang

Baniahmad

et al. 2009

FEBS Letters

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a b s t r a c tThe Bcl-2 associated athanogene 1M (Bag-1M) is known to repress the transactivation of the glucocorticoid receptor (GR). We report here that Bag-1M inhibits the action of GR via recruitment of corepressors, including nuclear receptor corepressor (NcoR) and silencing mediator for retinoic acid and thyroid hormone receptor (SMRT), and histone deacetylase (HDAC)3 to the genomic response element of a glucocorticoid-regulated human metallothionein IIa (hMTIIa) gene. A mutant GR lacking the interaction with BAG-1M fails to recruit the corepressors NcoR and SMRT. RNAi-mediated knock down of corepressors and the use of HDAC inhibitor relieved Bag-1M-induced repression on the transactivation of the GR. In addition, Bag-1M is not involved in the degradation of the receptor. These findings indicate a novel mechanism by which Bag-1M acts as a corepressor and downregulates the activity of the GR. Structured summary:

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The BAG-1 cochaperone is a negative regulator of p73-dependent transcription

Cited by 10 publications

References 75 publications

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

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

BAG-1 overexpression attenuates luminal apoptosis in MCF-10A mammary epithelial cells through enhanced RAF-1 activation

Bag‐1M inhibits the transactivation of the glucocorticoid receptor via recruitment of corepressors

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