BAG-1: a multifunctional regulator of cell growth and survival

Townsend, Paul A.; Cutress, Ramsey I.; Sharp, Adam; Brimmell, Matthew; Packham, Graham

doi:10.1016/s0304-419x(03)00002-7

Cited by 82 publications

(132 citation statements)

References 101 publications

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“…It is these functions and how they are regulated that are of major interest. For example, we have shown that BAG4 expression in plants confers tolerance to a wide range of abiotic stresses, including cold, UV light, oxidants, drought, and salt, which parallels mammalian studies involving BAG1 (Townsend et al, 2003;Doukhanina et al, 2006;Hoang et al, 2015). Arabidopsis BAG6 was previously shown to be associated with calmodulin and calmodulin-dependent signaling (Kang et al, 2006).…”

Section: Discussionsupporting

confidence: 55%

Aspartyl Protease-Mediated Cleavage of BAG6 Is Necessary for Autophagy and Fungal Resistance in Plants

et al. 2016

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The Bcl-2-associated athanogene (BAG) family is an evolutionarily conserved group of cochaperones that modulate numerous cellular processes. Previously we found that Arabidopsis thaliana BAG6 is required for basal immunity against the fungal phytopathogen Botrytis cinerea. However, the mechanisms by which BAG6 controls immunity are obscure. Here, we address this important question by determining the molecular mechanisms responsible for BAG6-mediated basal resistance. We show that Arabidopsis BAG6 is cleaved in vivo in a caspase-1-like-dependent manner and via a combination of pulldowns, mass spectrometry, yeast two-hybrid assays, and chemical genomics, we demonstrate that BAG6 interacts with a C2 GRAM domain protein (BAGP1) and an aspartyl protease (APCB1), both of which are required for BAG6 processing. Furthermore, fluorescence and transmission electron microscopy established that BAG6 cleavage triggers autophagy in the host that coincides with disease resistance. Targeted inactivation of BAGP1 or APCB1 results in the blocking of BAG6 processing and loss of resistance. Mutation of the cleavage site blocks cleavage and inhibits autophagy in plants; disease resistance is also compromised. Taken together, these results identify a mechanism that couples an aspartyl protease with a molecular cochaperone to trigger autophagy and plant defense, providing a key link between fungal recognition and the induction of cell death and resistance.

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Section: Discussionsupporting

confidence: 55%

Aspartyl Protease-Mediated Cleavage of BAG6 Is Necessary for Autophagy and Fungal Resistance in Plants

et al. 2016

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“…BAG-1 (BCL-2-associated anthanogene 1) is a prosurvival protein that was first identified as a binding partner of BCL-2 (Takayama et al, 1995) and the activated glucocorticoid receptor (Zeiner and Gehring, 1995), and has subsequently been shown to have pleiotropic effects on a diverse range of cellular responses, including apoptosis, transcription, proliferation and signaling (Townsend et al, 2003b).…”

Section: Introductionmentioning

confidence: 99%

“…The BAG-1 gene encodes three major protein isoforms: designated BAG-1S (36 kDa), BAG-1M (46 kDa) and BAG-1L (50 kDa), which are generated by alternate translation initiation from a single mRNA molecule and share a common carboxy terminus (Townsend et al, 2003b). The latter contains the 'BAG domain', a region that has a key role in mediating many of BAG-1's cellular effects.…”

Section: Introductionmentioning

confidence: 99%

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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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“…Bcl-2 associated athanogene (BAG-1) is a multifunctional protein that interacts with multiple cellular targets and modulates a wide range of cellular processes (Alberti et al, 2003;Townsend et al, 2003aTownsend et al, , 2005Gehring, 2004). Overexpression of BAG-1 protects cells from various apoptotic stimuli, enhances proliferation and metastasis, and modulates the transcriptional activity of a variety of nuclear hormone receptors.…”

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confidence: 99%

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

O’Connor

Brimmell

et al. 2009

Br J Cancer

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High-level expression of Bcl-2 associated athanogene (BAG-1) protects cancer cells from stress-induced cell death and growth inhibition. These protective effects of BAG-1 are dependent on interactions with the HSC70 and HSP70 chaperones. However, the key stress-response molecules that are regulated by a BAG-1/chaperone mechanism have not been identified. In this study, we investigated the effects of BAG-1 overexpression on the function of p53 family proteins, p53, p63 and p73. Overexpression of BAG-1 isoforms interfered with the transactivating activity of p73 and p63, but had modest and variable effects on p53-dependent transcription. p73 and BAG-1 interacted in intact cells and overexpression of BAG-1 decreased the expression of p73. siRNAmediated ablation of endogenous BAG-1 increased the activity of a p73-responsive promoter and this was reversed by knock-down of p73. The ability of BAG-1 to modulate p73 activity and expression, and to interact with p73 were dependent on amino acid residues required for the interaction of BAG-1 with HSC70 and HSP70. These results show that BAG-1 inhibits the transactivating functions of p73 and provide new insight into the mechanisms that control the expression of p73. Inhibition of p73 function may be one mechanism that contributes to the pro-survival activity of BAG-1.

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BAG-1: a multifunctional regulator of cell growth and survival

Cited by 82 publications

References 101 publications

Aspartyl Protease-Mediated Cleavage of BAG6 Is Necessary for Autophagy and Fungal Resistance in Plants

Aspartyl Protease-Mediated Cleavage of BAG6 Is Necessary for Autophagy and Fungal Resistance in Plants

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

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

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