Alternative titles; symbols
HGNC Approved Gene Symbol: BAG4
Cytogenetic location: 8p11.23 Genomic coordinates (GRCh38): 8:38,176,855-38,213,301 (from NCBI)
Tumor necrosis factor receptor-1 (TNFR1; 191190) and several other members of the TNF receptor superfamily, such as DR3 (603366), contain intracellular death domains and are capable of triggering apoptosis when activated by their respective ligands. However, TNFR1 self-associates and signals independently of ligand when overexpressed. Jiang et al. (1999) suggested the existence of a cellular mechanism to protect against ligand-independent signaling by TNFR1 and other death domain receptors. Using a yeast 2-hybrid assay with DR3 as bait, these authors identified a cDNA encoding a protein that they designated 'silencer of death domains' (SODD). The predicted 457-amino acid SODD protein migrates as a doublet of 60 kD on Western blots of mammalian cell extracts. Coimmunoprecipitation studies revealed that SODD is associated with TNFR1 in vivo. TNF treatment of cells released SODD from TNFR1, permitting the recruitment of proteins such as TRADD (603500) and TRAF2 (601895) to the active TNFR1 signaling complex. Jiang et al. (1999) proposed that SODD is a negative regulatory protein that is normally associated with the death domain of TNFR1, inhibiting the intrinsic self-aggregation properties of the death domain and maintaining TNFR1 in an inactive, monomeric state. This inhibition is relieved by TNF-mediated receptor crosslinking, which triggers the rapid release of SODD, allowing the death domains of TNFR1 to self-associate and bind other proteins to form an active TNFR1 signaling complex. These authors found that SODD also interacted with DR3 in yeast 2-hybrid assays, suggesting that SODD association may be representative of a general mechanism for preventing spontaneous signaling by death domain-containing receptors.
BAG1 (601497) binds the ATPase domains of Hsp70 (see 140550) and Hsc70 (600816), modulating their chaperone activity. See BAG2 (603882). Takayama et al. (1999) identified cDNAs corresponding to BAG4 and 3 other BAG1-like proteins. These authors suggested that interactions with various BAG family proteins allow opportunities for specification and diversification of Hsp70/Hsc70 chaperone functions.
Pancreatic cancer cells are resistant to TNFA-mediated apoptosis. By Northern blot analysis, Ozawa et al. (2000) detected a 5-fold increased expression of 3.5-kb SODD transcripts in pancreatic cancer cells and pancreatic cancer cell lines compared with normal pancreatic cells. Other gastrointestinal cancers (liver, esophagus, stomach, and colon) showed no increased SODD expression. In situ hybridization analysis revealed expression of SODD in the cytoplasm of cancer cells.
By array CGH, Yang et al. (2006) analyzed the copy number and expression level of genes in the 8p12-p11 amplicon in 22 human breast cancer (114480) specimens and 7 breast cancer cell lines. Of the 21 potential genes identified, PCR analysis and functional analysis indicated that 3 genes, LSM1 (607281), BAG4, and C8ORF4 (607702), are breast cancer oncogenes that can work in combination to influence a transformed phenotype in human mammary epithelial cells.
Hasson et al. (2013) elucidated regulators that have an impact on parkin (PARK2; 602544) translocation to damaged mitochondria with genomewide small interfering RNA (siRNA) screens coupled to high-content microscopy. Screening yielded gene candidates involved in diverse cellular processes that were subsequently validated in low-throughput assays. This led to characterization of TOMM7 (607980) as essential for stabilizing PINK1 (608309) on the outer mitochondrial membrane following mitochondrial damage. Hasson et al. (2013) also discovered that HSPA1L (140559) and BAG4 have mutually opposing roles in the regulation of parkin translocation. The screens revealed that SIAH3 (615609), found to localize to mitochondria, inhibits PINK1 accumulation after mitochondrial insult, reducing parkin translocation.
The BAG4 gene resides on chromosome 8p11 (Yang et al., 2006).
Hasson, S. A., Kane, L. A., Yamano, K., Huang, C.-H., Sliter, D. A., Buehler, E., Wang, C., Heman-Ackah, S. M., Hessa, T., Guha, R., Martin, S. E., Youle, R. J. High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy. Nature 504: 291-295, 2013. [PubMed: 24270810] [Full Text: https://doi.org/10.1038/nature12748]
Jiang, Y., Woronicz, J. D., Liu, W., Goeddel, D. V. Prevention of constitutive TNF receptor 1 signaling by silencer of death domains. Science 283: 543-546, 1999. Note: Erratum: Science 283: 1852 only, 1999. [PubMed: 9915703] [Full Text: https://doi.org/10.1126/science.283.5401.543]
Ozawa, F., Friess, H., Zimmermann, A., Kleeff, J., Buchler, M. W. Enhanced expression of silencer of death domains (SODD/BAG-4) in pancreatic cancer. Biochem. Biophys. Res. Commun. 271: 409-413, 2000. [PubMed: 10799310] [Full Text: https://doi.org/10.1006/bbrc.2000.2610]
Takayama, S., Xie, Z., Reed, J. C. An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators. J. Biol. Chem. 274: 781-786, 1999. [PubMed: 9873016] [Full Text: https://doi.org/10.1074/jbc.274.2.781]
Yang, Z. Q., Streicher, K. L., Ray, M. E., Abrams, J., Ethier, S. P. Multiple interacting oncogenes on the 8p11-p12 amplicon in human breast cancer. Cancer Res. 66: 11632-11643, 2006. [PubMed: 17178857] [Full Text: https://doi.org/10.1158/0008-5472.CAN-06-2946]