A BAG's life: Every connection matters in cancer

Mariotto, Elena; Viola, Giampietro; Zanon, Carlo; Aveic, Sanja

doi:10.1016/j.pharmthera.2020.107498

Cited by 34 publications

(41 citation statements)

References 180 publications

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“…A structural analysis of the BAG-HSC70 complex revealed that the BAG domain forms a three-helix bundle and binds the HSP70 NBD, which induces a conformational change similar to that induced by GrpE [184]. The six human BAG proteins contain different accessory domains, which specify their cellular roles [185]. Of interest to this review, BAG-1 and BAG-6 have been linked to UPS-mediated degradation of misfolded proteins.…”

Section: Regulation Of Chaperone Activitymentioning

confidence: 99%

“…Of interest to this review, BAG-1 and BAG-6 have been linked to UPS-mediated degradation of misfolded proteins. Importantly, they both contain N-terminal UBL-domains that bind the 19S regulatory particle of the 26S proteasome ( Figure 2 A,B), while BAG-6 also contains a UBL-like domain related to substrate binding [ 185 , 186 ].…”

Section: Co-chaperones Decide the Fate Of Hsp70-bound Substratesmentioning

confidence: 99%

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Co-Chaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome

et al. 2020

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Protein homeostasis (proteostasis) is essential for the cell and is maintained by a highly conserved protein quality control (PQC) system, which triages newly synthesized, mislocalized and misfolded proteins. The ubiquitin-proteasome system (UPS), molecular chaperones, and co-chaperones are vital PQC elements that work together to facilitate degradation of misfolded and toxic protein species through the 26S proteasome. However, the underlying mechanisms are complex and remain partly unclear. Here, we provide an overview of the current knowledge on the co-chaperones that directly take part in targeting and delivery of PQC substrates for degradation. While J-domain proteins (JDPs) target substrates for the heat shock protein 70 (HSP70) chaperones, nucleotide-exchange factors (NEFs) deliver HSP70-bound substrates to the proteasome. So far, three NEFs have been established in proteasomal delivery: HSP110 and the ubiquitin-like (UBL) domain proteins BAG-1 and BAG-6, the latter acting as a chaperone itself and carrying its substrates directly to the proteasome. A better understanding of the individual delivery pathways will improve our ability to regulate the triage, and thus regulate the fate of aberrant proteins involved in cell stress and disease, examples of which are given throughout the review.

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Section: Regulation Of Chaperone Activitymentioning

confidence: 99%

Section: Co-chaperones Decide the Fate Of Hsp70-bound Substratesmentioning

confidence: 99%

Co-Chaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome

et al. 2020

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“…Studies found that Hsp70 suppressed apoptosis through multiple pathways, like preventing Bax translocation, preventing oligomerization of apoptotic protease activating factor 1 (APAF1), neutralizing the apoptosis-inducing factor (AIF) and inhibiting the activation of Caspase-3 [44][45][46][47][48]. Moreover, the BAG family is well known for its capability in preventing cell death through interaction with Bcl-2, which plays a prominent role in suppressing apoptosis and enhancing cell survival in response to diverse apoptotic stimuli [5,49]. Thus, BAG2 might inhibit cell apoptosis in HCC via enhancing the anti-apoptotic function of Bcl-2 [50].…”

Section: Discussionmentioning

confidence: 99%

“…The function of these proteins have been well studied in neurodegenerative disorders like Alzheimer's and Parkinson's disease, but recently the family has become a focus in canceroriented research [5]. BAG2 shares a C-terminal conserved region (the BAG domain) with other members of the family, allowing it to bind the HSP70 family of molecular chaperones [5]. As a member of the BAG family, BAG2 is also found to play an essential role in several types of cancer [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Bcl-2 Associated Athanogene 2 (BAG2) is Associated With Progression and Prognosis of Hepatocellular Carcinoma: A Bioinformatics-Based Analysis

Zhang¹,

Liu²,

Li³

et al. 2021

Pathol. Oncol. Res.

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Background: Bcl-2 associated athanogene2 (BAG2) is reported to act as an oncogene or a tumor-suppressor in tumors in a context-dependent way; however, its function in hepatocellular carcinoma (HCC) remains unclear.Methods: Immunohistochemistry (IHC) staining, cell counting kit-8 (CCK-8) assay, apoptotic assay, cell invasion assay and a set of bioinformatics tools were integrated to analyze the role of BAG2 in hepatocellular carcinoma.Results: BAG2 was significantly up-regulated in HCC. Prognostic analysis indicated that HCC patients with high expression of BAG2 had significantly shorter overall survival, progression free survival and disease specific survival. Besides, silencing BAG2 in HCC cells impaired cell proliferation, facilitated apoptosis and repressed invasion of the cells. Bioinformatics analysis showed that BAG2 might regulate ribosome biogenesis in HCC.Conclusion: This study revealed that the up-regulated BAG2 in HCC was associated with a worse prognosis and might favor the progression of the disease.

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“…AKT kinases (AKT1-3) are localized downstream of PI3Ks and activates ERα [54]. AKT phosphorylates many transcription factors and also controls proliferation and survival pathways through phosphorylation [56]. mTOR is one of the major regulators of autophagy and is a downstream effector of AKT and PI3K [38].…”

Section: Discussionmentioning

confidence: 99%

Co-Chaperone Bag-1 Plays a Role in the Autophagy-Dependent Cell Survival through Beclin 1 Interaction

et al. 2021

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Expression levels of the major mammalian autophagy regulator Beclin 1 and its interaction with Bcl-2 regulate the switch between autophagic cell survival and apoptotic cell death pathways. However, some of the regulators and the precise mechanisms of these processes still remain elusive. Bag-1 (Bcl-2 associated athanogene-1), a member of BAG family proteins, is a multifunctional pro-survival molecule that possesses critical functions in vital cellular pathways. Herein, we report the role of Bag-1 on Bcl-2/Beclin 1 crosstalk through indirectly interacting with Beclin 1. Pull-down experiments suggested a molecular interaction between Bag-1 and Beclin 1 in breast cancer cell lines. On the other hand, in vitro binding assays showed that Bag-1/Beclin 1 interaction does not occur directly but occurs through a mediator molecule. Bag-1 interaction with p-Beclin 1 (T119), indicator of early autophagy, is increased during nutrient starvation suggesting involvement of Bag-1 in the autophagic regulation. Furthermore, CRISPR/Cas9-mediated Bag-1 knock-out in MCF-7 cells hampered cell survival and proliferation and resulted in decreased levels of total LC3 under starvation. Collectively, we suggest that Bag-1 modulates cell survival/death decision through maintaining macroautophagy as a component of Beclin 1-associated complexes.

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A BAG's life: Every connection matters in cancer

Cited by 34 publications

References 180 publications

Co-Chaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome

Co-Chaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome

Bcl-2 Associated Athanogene 2 (BAG2) is Associated With Progression and Prognosis of Hepatocellular Carcinoma: A Bioinformatics-Based Analysis

Co-Chaperone Bag-1 Plays a Role in the Autophagy-Dependent Cell Survival through Beclin 1 Interaction

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