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derstood. Here, we found that BAG2, a protein of Bcl-2 associated athanogene (BAG) family, promotes mutp53 accumulation and GOF in tumors. Mechanistically, BAG2 binds to mutp53 and translocates to the nucleus to inhibit the MDM2-mutp53 interaction, and MDM2-mediated ubiquitination and degradation of mutp53. Thus, BAG2 promotes mutp53 accumulation and GOF in tumor growth, metastasis and chemoresistance. BAG2 is frequently overexpressed in tumors. BAG2 overexpression is associated with poor prognosis in patients and mutp53 accumulation in tumors. These findings revealed a novel and important mechanism for mutp53 accumulation and GOF in tumors, and also uncovered an important role of BAG2 in tumorigenesis through promoting mutp53 accumulation and GOF.

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function is regulated by phosphorylation, and its hyperphosphorylated forms are significantly more abundant in AD brain. Little is known about the relationship between nAChR and phospho-tau degradation machinery. Activation of nAChRs has been reported to increase and decrease tau phosphorylation levels, and the mechanisms responsible for this discrepancy are not presently understood. The co-chaperone BAG2 is capable of regulating phospho-tau levels via protein degradation. In SH-SY5Y cell line and rat primary hippocampal cell culture low endogenous BAG2 levels constitute an intracellular environment conducive to nicotine-induced accumulation of phosphorylated tau protein. Further, nicotine treatment inhibited endogenous expression of BAG2, resulting in increased levels of phosphorylated tau indistinguishable from those induced by BAG2 knockdown. Conversely, overexpression of BAG2 is conducive to a nicotine-induced reduction in cellular levels of phosphorylated tau protein. In both cases the effect of nicotine was p38MAPK-dependent, while the alpha7 antagonist MLA was synthetic to nicotine treatment, either increasing levels of phospho-Tau in the absence of BAG2, or further decreasing the levels of phospho-Tau in the presence of BAG2. Taken together, these findings reconcile the apparently contradictory effects of nicotine on tau phosphorylation by suggesting a role for BAG2 as an important regulator of p38-dependent tau kinase activity and phospho-tau degradation in response to nicotinic receptor stimulation. Thus, we report that BAG2 expression dictates a functional intracellular switch between the p38-dependent functions of nicotine on tau phosphorylation levels via the alpha7 nicotinic receptor.

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t cellular responses to stress, including cell cycle arrest and apoptosis. Here, we use SH-SY5Y neuroblastoma cells to characterize BAG2 expression and regulation and investigate the involvement of BAG2 in Abeta1-42-mediated neurotrophism or neurotoxicity in the context of differentiation. We report that BAG2 is upregulated on differentiation of SH-SY5Y cells into neuron-like cells. This increase in BAG2 expression is accompanied by a change in response to treatment with Abeta1-42 from neurotrophic to neurotoxic. Further, overexpression of BAG2 in undifferentiated SH-SY5Y cells was sufficient to induce the change from neurotrophic to neurotoxic response. Of several transcription factors queried, the putative BAG2 promoter had a higher-than-expected occurrence of response elements (RE) for nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB). Treatment with JSH-23, a potent inhibitor of NF-kappaB, caused a marked increase in BAG2 mRNA expression, suggesting that NF-kappaB is a repressor of BAG2 transcription in undifferentiated SH-SY5Y cells. Together, these data suggest that NF-kappaB-mediated modulation of BAG2 expression constitutes a "switch" that regulates the shift between the neurotrophic and neurotoxic effects of Abeta1-42.