Disease relevance of BAG4

• BAG-4 tagged with green fluorescent protein (GFP) or FLAG was localized both in cytoplasm of mouse BNLCL.2 liver cells and human liver hepatoma HepG2 cells [1].
• Thus, LSM1, BAG4, and C8orf4 are breast cancer oncogenes that can work in combination to influence the transformed phenotype in human mammary epithelial cells [2].
• In this report, we demonstrate increased SODD mRNA levels in pancreatic cancer (n = 30) in comparison to normal control tissues (n = 20, P < 0.01) [3].
• In contrast, SODD mRNA levels were not different (P > 0.05) in four other gastrointestinal cancers (liver, esophagus, stomach, colon) compared with the corresponding normal tissues [3].

High impact information on BAG4

• This apparent paradox may be explained by silencer of death domains (SODD), a widely expressed approximately 60-kilodalton protein that was found to be associated with the death domain of TNF-R1 [4].
• SODD also interacted with death receptor-3 (DR3), another member of the TNF receptor superfamily [4].
• Protection of cells against heat shock as mediated by the Hsp70 system and against staurosporine-induced apoptosis was independent of SODD [5].
• In normal human kidney SODD is expressed in glomerular endothelial cells where it colocalizes with TNFR1 [6].
• BAG4 BD thus represents a prototype of the minimal functional fragment that is capable of binding to Hsc70 and modulating its chaperone activity [7].

Biological context of BAG4

• Stable transfection of a SODD/BAG-4 cDNA leads to increased levels of the full-length 70-kDa protein and additional C-terminal fragments as well as altered expression of BAG-1 [8].
• We therefore studied the expression of DR3 in human kidney, and report that this death receptor is up-regulated in renal tubular epithelial cells and endothelial cells of some interlobular arteries, in parallel with SODD, during acute transplant rejection [6].
• This SODD protein is not involved in the regulation of cell survival after radiation or TNFalpha treatment but rather in altered TNFR1 shedding [9].
• We further showed that three of these genes (LSM1, BAG4, and C8orf4) induce transformed phenotypes when overexpressed in MCF-10A cells, and overexpression of these genes in combination influences the growth factor independence phenotype and the ability of the cells to grow under anchorage-independent conditions [2].
• Linkage and association analyses of these SNPs yield suggestive results for markers in FGFR1 (recessive multipoint HLOD 1.07) and BAG4 (recessive multipoint HLOD 1.31) [10].

Anatomical context of BAG4

• In contrast, a modest decrease in SODD transcript was observed in peripheral blood lymphocytes [11].
• IkappaB/NF-kappaB mediated cisplatin resistance in HeLa cells after low-dose gamma-irradiation is associated with altered SODD expression [12].
• In HeLa/B cells, reduced expression of the 50 kDa silencer of death domain, SODD, is accompanied by constitutive overexpression of a 40-42 kDa SODD-like protein [12].

Associations of BAG4 with chemical compounds

• During acute rejection both SODD and TNFR1 are lost from glomeruli, but we found strong expression of SODD on the luminal surface of tubular epithelial cells [6].
• Inhibition of TNFR1 release by the metalloprotease inhibitor BB-2516 results in a significant increase of the 42 kDa SODD protein without affecting cell survival in sensitive or resistant HT cells [9].

Physical interactions of BAG4

• A homology model of the SODD-BAG/HSP70 complex reveals additional possible interactions that are specific for the SODD subfamily of BAG domains while the overall geometry of the complex remains the same [13].

Regulatory relationships of BAG4

• In addition, overexpression of SODD suppresses TNF-alpha-induced cell death [3].

Other interactions of BAG4

• Altered signaling of TNFalpha-TNFR1 and SODD/BAG4 is responsible for radioresistance in human HT-R15 cells [9].
• Taken together, these observations suggested that camptothecin and VP-16 induced rapid aggregation of DR4 and DR3, but paradoxically, the importance of these events in signaling apoptosis is uncertain, because the kinetics of apoptosis were unaffected, even in the presence of a high expression level of SODD, FADD-DN, TRADD-ND, and DAP3-DN [14].
• The SODD BAG domain is thus indeed smaller than the homologous domain in Bag1 defining a new subfamily of BAG domains [13].
• We examined the expression of SODD mRNA during TNF-induced apoptosis [11].
• Examples are BAG4, PAX3 and CCNI, respectively [15].

Analytical, diagnostic and therapeutic context of BAG4

• Immunoprecipitation experiments confirmed that BAG-4 interacts with Hsc70/Hsp90 in HepG2 cells [1].
• In situ hybridization analysis revealed SODD expression predominantly in the cancer cells within the pancreatic tumor mass [3].
• Consistent with this, WT and mutant full-length TNFRSF1A formed cytoplasmic aggregates that co-localized with ubiquitin and chaperones, and with the signal transducer TRADD, but not with the inhibitor, silencer of death domain (SODD) [16].

References