Apoptosis inhibition in cancer cells: A novel molecular pathway that involves BAG3 protein

Rosati, Alessandra; Ammirante, Massimo; Gentilella, Antonio; Basile, Anna; Festa, Michela; Pascale, Maria; Marzullo, Liberato; Belisario, Maria Antonietta; Tosco, Alessandra; Franceschelli, Silvia; Moltedo, Ornella; Pagliuca, Gabriella; Lerose, Rosa; Turco, Maria Caterina

doi:10.1016/j.biocel.2007.03.007

Cited by 123 publications

(138 citation statements)

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“…For example, the finding that BAG3 was up-regulated in Tam treated cells is very interesting, as it was recently shown that BAG3 has anti-apoptotic activity, and that expression of BAG3 in neoplastic cells sustains cell survival in response to stress inducing factors. It is also believed that BAG3 could be responsible for impairing response to therapy, and could represent a novel therapeutic target [57]. The other up-regulated protein, Poly(rC)-binding protein 1, is a nucleic acid binding protein that functions as an accelerator of mRNA metabolic processes and has roles in mRNA stabilization, translational activation and translational silencing [58,59].…”

Section: Biological Relevance Of Differentially Expressed Proteinsmentioning

confidence: 99%

Differential protein expression analysis using stable isotope labeling and PQD linear ion trap MS technology

Armenta

Hoeschele

Lazar

2009

J. Am. Soc. Mass Spectrom.

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An isotope tags for relative and absolute quantitation (iTRAQ)-based reversed-phase liquid chromatography (RPLC)-tandem mass spectrometry (MS/MS) method was developed for differential protein expression profiling in complex cellular extracts. The estrogen positive MCF-7 cell line, cultured in the presence of 17␤-estradiol (E2) and tamoxifen (Tam), was used as a model system. MS analysis was performed with a linear trap quadrupole (LTQ) instrument operated by using pulsed Q dissociation (PQD) detection. Optimization experiments were conducted to maximize the iTRAQ labeling efficiency and the number of quantified proteins. MS data filtering criteria were chosen to result in a false positive identification rate of Ͻ4%. The reproducibility of protein identifications was ϳ60%-67% between duplicate, and ϳ50% among triplicate LC-MS/MS runs, respectively. The run-to-run reproducibility, in terms of relative standard deviations (RSD) of global mean iTRAQ ratios, was better than 10%. The quantitation accuracy improved with the number of peptides used for protein identification. From a total of 530 identified proteins (P Ͻ 0.001) in the E2/Tam treated MCF-7 cells, a list of 255 proteins (quantified by at least two peptides) was generated for differential expression analysis. A method was developed for the selection, normalization, and statistical evaluation of such datasets. An approximate ϳ2-fold change in protein expression levels was necessary for a protein to be selected as a biomarker candidate. According to this data processing strategy, ϳ16 proteins involved in biological processes such as apoptosis, RNA processing/metabolism, DNA replication/transcription/repair, cell proliferation and metastasis, were found to be up-or down-regulated. R ecently, two-dimensional liquid chromatography (2DLC) with tandem MS detection has emerged as an attractive technology for quantitative proteomic profiling of complex cellular extracts [1][2][3][4]. Stable isotope labeling and label-free quantitation strategies have been explored [4 -13]. Isotope labeling approaches rely on the covalent attachment of stable isotope tags to specific amino acid residues of proteins or peptides during metabolic, enzymatic, or chemical processes. Label-free quantitation methods rely on measuring peak areas, intensities, or spectral counts, and benefit from not having to chemically alter the sample. Throughput, however, is lower, and quantitation errors are higher, as the samples are processed independently. Among chemical labeling techniques, isotope tags for relative and absolute quantitation (iTRAQ) has received much attention [14 -30]. In this approach, peptides are labeled with isobaric tags at the N-terminus and the lysine side chains. MS/MS fragmentation produces signature ions that can be used to obtain quantitative information. Perhaps the most attractive advantage of this approach is that it can be used for the simultaneous quantification (relative or absolute) of up to four/eight different samples. Simplicity, of course, is an added benefit.A...

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Section: Biological Relevance Of Differentially Expressed Proteinsmentioning

confidence: 99%

Differential protein expression analysis using stable isotope labeling and PQD linear ion trap MS technology

Armenta

Hoeschele

Lazar

2009

J. Am. Soc. Mass Spectrom.

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“…B cell CLL/lymphoma 2 (BCL-2)-interacting cell death suppressor (BIS; also known as BCL2-associated athanogene [BAG]3 or carboxyamido-triazole-stressed [CAIR]-1), was originally identified based on its ability to interact with the BCL-2 protein and enhance its anti-apoptotic activity [10]. Recent studies have shown that BIS is involved in the regulation of cell survival in various cellular environments [11][12][13][14], as well as in protein quality during ageing [15,16]. BIS upregulation has been observed in cells exposed to a variety of stresses [17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Aggravation of diabetic nephropathy in BCL-2 interacting cell death suppressor (BIS)-haploinsufficient mice together with impaired induction of superoxide dismutase (SOD) activity

et al. 2013

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Aims/hypothesis B cell CLL/lymphoma 2 (BCL-2)-interacting cell death suppressor (BIS), known as an anti-stress and antiapoptotic protein, has been reported to modulate susceptibility to oxidative stress. This study investigated the potential role of BIS as an antioxidant protein in diabetic nephropathy. Methods Diabetes was induced in BIS-heterozygote (BIS-HT) mice via streptozotocin injections and the resulting phenotypes were compared with those of BIS-wild-type (BIS-WT) mice over the 20 weeks following diabetes induction.Results Renal injuries, represented by increased plasma creatinine levels and increased albuminuria, were greater in diabetic BIS-HT mice than in diabetic BIS-WT mice, and were accompanied by a significant increase in reactive oxygen species (ROS) and oxidative stress markers. Moreover, renal pathological changes and the apoptotic process were accelerated in diabetic BIS-HT mice compared with diabetic BIS-WT mice with the same degree of hyperglycaemia; all were restored by 4-hydroxy-2,2,6,6-tetramethylpiperidine-Noxyl (tempol) treatment. The levels of NADPH oxidase and related proteins were not significantly higher in diabetic BIS-HT mice compared with diabetic BIS-WT mice. However, levels of superoxide dismutase (SOD)1 and SOD2 increased on the induction of diabetes in BIS-WT mice but not in BIS-HT mice, correlating with the total SOD activity. An in vitro study showed that knockdown of BIS production also resulted in impaired induction of SOD activity as well as SOD levels in HK-2 and NMS cells, concomitant with significant ROS accumulation. Conclusion/interpretation Our results suggest that the decreased antioxidant capacity of BIS aggravates diabetic nephropathy in diabetic BIS-HT mice, possibly as a result of the disruption in the regulation of SOD protein quality under oxidative stress. Electronic supplementary material The online version of this article (doi:10.1007/s00125-013-3064-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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“…All BAG proteins are characterized by a conserved domain of 110-124 amino acids (BAG domain) (3, 10) through which they bind to the HSC70/HSP70 ATPase domain regulating the heat shock protein (HSP) polypeptide folding activity (2,11). In addition, BAG3 contains a WW domain and a proline-rich repeat (PXXP) through which it interacts with other partners, such as phospholipase C (PLC)-γ (12) and Akt kinase (13).…”

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confidence: 99%

“…BAG3 is a 74-kDa cytoplasmic protein mainly localized in the rough endoplasmic reticulum; a slightly different molecular weight or a doublet form can be observed in some cell types and/or following cell exposition to stressors (11,14,15). In humans, bag3 is constitutively expressed in myocytes and a few other normal cell types and in several tumors (leukemia and lymphoma, myeloma, and pancreas and thyroid carcinomas) (11,(16)(17)(18)(19)(20).…”

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confidence: 99%

IKKγ protein is a target of BAG3 regulatory activity in human tumor growth

Ammirante

Rosati

Arra³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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BAG3, a member of the BAG family of heat shock protein (HSP) 70 cochaperones, is expressed in response to stressful stimuli in a number of normal cell types and constitutively in a variety of tumors, including pancreas carcinomas, lymphocytic and myeloblastic leukemias, and thyroid carcinomas. Down-regulation of BAG3 results in cell death, but the underlying molecular mechanisms are still elusive. Here, we investigated the molecular mechanism of BAG3-dependent survival in human osteosarcoma (SAOS-2) and melanoma (M14) cells. We show that bag3 overexpression in tumors promotes survival through the NF-κB pathway. Indeed, we demonstrate that BAG3 alters the interaction between HSP70 and IKKγ, increasing availability of IKKγ and protecting it from proteasome-dependent degradation; this, in turn, results in increased NF-κB activity and survival. These results identify bag3 as a potential target for anticancer therapies in those tumors in which this gene is constitutively expressed. As a proof of principle, we show that treatment of a mouse xenograft tumor model with bag3siRNA-adenovirus that down-regulates bag3 results in reduced tumor growth and increased animal survival.BAG3 | IKK-gamma | apoptosis

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Apoptosis inhibition in cancer cells: A novel molecular pathway that involves BAG3 protein

Cited by 123 publications

References 42 publications

Differential protein expression analysis using stable isotope labeling and PQD linear ion trap MS technology

Differential protein expression analysis using stable isotope labeling and PQD linear ion trap MS technology

Aggravation of diabetic nephropathy in BCL-2 interacting cell death suppressor (BIS)-haploinsufficient mice together with impaired induction of superoxide dismutase (SOD) activity

IKKγ protein is a target of BAG3 regulatory activity in human tumor growth

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