Alternative titles; symbols
HGNC Approved Gene Symbol: BAG1
Cytogenetic location: 9p13.3 Genomic coordinates (GRCh38): 9:33,252,471-33,264,708 (from NCBI)
The oncogene BCL2 (151430) is a membrane protein that blocks a step in a pathway leading to apoptosis. Takayama et al. (1995) used interaction cloning to identify Bag1, a mouse protein that binds to Bcl2. The Bag1 protein is rich in glutamic acid residues.
By screening a human liver expression library with activated glucocorticoid receptor (GCCR; 138040), Zeiner and Gehring (1995) cloned BAG1, which they called RAP46. The deduced 274-amino acid protein has a calculated molecular mass of 31 kD. It had an apparent molecular mass of 46 kD by SDS-PAGE. Northern blot analysis detected a 1.4-kb Rap46 transcript in all mouse tissues examined.
Takayama et al. (1996) cloned human BAG1 cDNAs from a fetal brain cDNA library using the mouse cDNA as a probe. The human cDNA encodes a predicted 274-amino acid protein, 55 residues longer at the N-terminal end than the mouse protein. The human BAG1 gene is 80% identical to the mouse gene sequence. The human protein is also highly acidic, with a pI of 5.3.
Takayama et al. (1995) found that overexpression of recombinant Bag1 in 3T3 fibroblasts prevented them from undergoing apoptosis when deprived of serum.
Zeiner and Gehring (1995) found that recombinant RAP46 interacted with activated glucocorticoid, androgen (AR; 313700), estrogen (see ESR1; 133430), and progesterone (PGR; 607311) receptors. Binding was dependent on receptor activation (i.e., release from heat shock proteins), but did not require the presence of receptor ligands. RAP46 showed a high affinity for estrogen receptor.
Wang et al. (1996) stated that overproduction of BCL2 occurs frequently in human cancers and contributes to tumor radio- and chemoresistance by blocking apoptosis induced by genotoxic injury and other types of damage. Conversely, reduced levels of BCL2 have been associated with higher rates of spontaneous and inducible apoptosis in circulating lymphocytes of persons infected with HIV and some other viruses. The BCL2-interacting protein, BAG1, enhances the anti-apoptotic effects of BCL2. Like BAG1, the serine/threonine protein kinase RAF1 (164760) also cooperates with BCL2 in suppressing apoptosis. Wang et al. (1996) showed that RAF1 and BAG1 specifically interact in vitro and in yeast 2-hybrid assays. RAF1 and BAG1 proteins can also be coimmunoprecipitated from mammalian cells and from insect cells infected with recombinant baculoviruses encoding these proteins.
Bardelli et al. (1996) found that BAG1 represents a link between growth factor receptors and anti-apoptotic mechanisms. They showed that BAG1 interacts with both the hepatocyte growth factor receptor (164860) and the platelet-derived growth factor receptor (173410) and, in both cases, enhances growth factor-mediated protection from apoptosis. The C-terminal region of the BAG1 protein was found to be responsible for binding to the receptors, but the entire BAG1 protein was required for protection from apoptosis.
Kullmann et al. (1998) demonstrated that mammalian Rap46 bound the hinge region of the glucocorticoid receptor and inhibited DNA binding and transactivation by the receptor. Overexpression of Rap46 in mouse thymoma cells inhibited glucocorticoid-induced apoptosis. Conversely, treatment with rapamycin, a RAP46 downregulator, enhanced glucocorticoid-induced apoptosis and transactivation.
Yang et al. (1999) cloned and characterized the human BAG1 gene promoter. Functional characterization of the BAG1 promoter in vivo demonstrated that gain-of-function p53 (191170) mutants derived from human tumors upregulated the transcription of BAG1 RNA and the expression of a reporter gene from the BAG1 promoter.
Takayama et al. (1996) assigned human BAG1 to chromosome 9 using a panel of somatic cell hybrid DNAs and localized it to 9p12 by fluorescence in situ hybridization.
By targeted deletion of the Bag1 gene in mice, Gotz et al. (2005) showed that Bag1 has an essential role in the survival of differentiating neurons and hematopoietic cells. While Bag1 +/- mice were viable and appeared normal, Bag1 -/- embryos were growth retarded by embryonic day 13.5 and died between embryonic days 12.5 and 13.5. Histologic analysis detected abnormalities in the fetal liver and forebrain corresponding to the onset of endogenous Bag1 expression. Fetal livers of Bag1 -/- embryos were smaller than those of Bag1 +/- or wildtype littermates, suggesting a defect in hematopoiesis. In the nervous system, formation of the telencephalic vesicles was severely disturbed. TUNEL and propidium-iodide staining indicated massive apoptosis in fetal liver and increased apoptosis in fetal brains compared with wildtype controls. Lack of Bag1 did not disturb the primary function of Akt (see AKT1; 164730) or Raf, but it was associated with absence of Bad (603167) phosphorylation and disturbance of a tripartite complex formed by Akt, Braf, and Bag1. Bag1 -/- embryos had reduced expression of members of the inhibitor of apoptosis (see BIRC2; 601712) family.
Maeng et al. (2008) found that transgenic mice with selective neuron-specific overexpression of Bag1 in the hippocampus did not have obvious motor, sensory, or learning impairments, but showed less anxious behavior and had higher spontaneous recovery rates from helplessness behavior compared to wildtype mice. These transgenic mice also recovered faster from tests designed to trigger hyperlocomotion or addictive behaviors. In contrast, heterozygous Bag1 +/- mice showed enhanced extreme behavioral responses and less recovery in similar tests. The data suggested that BAG1 may play a role in affective resilience, and perhaps regulates recovery from behavioral impairments observed in patients with bipolar affective disorder (see 125480). Maeng et al. (2008) postulated that the effects are mediated by BAG1 regulation of glucocorticoid receptor function.
Bardelli, A., Longati, P., Albero, D., Goruppi, S., Schneider, C., Ponzetto, C., Comoglio, P. M. HGF receptor associates with the anti-apoptotic protein BAG-1 and prevents cell death. EMBO J. 15: 6205-6212, 1996. [PubMed: 8947043]
Gotz, R., Wiese, S., Takayama, S., Camarero, G. C., Rossoll, W., Schweizer, U., Troppmair, J., Jablonka, S., Holtmann, B., Reed, J. C., Rapp, U. R., Sendtner, M. Bag1 is essential for differentiation and survival of hematopoietic and neuronal cells. Nature Neurosci. 8: 1169-1178, 2005. [PubMed: 16116448] [Full Text: https://doi.org/10.1038/nn1524]
Kullmann, M., Schneikert, J., Moll, J., Heck, S., Zeiner, M., Gehring, U., Cato, A. C. B. RAP46 is a negative regulator of glucocorticoid receptor action and hormone-induced apoptosis. J. Biol. Chem. 273: 14620-14625, 1998. [PubMed: 9603979] [Full Text: https://doi.org/10.1074/jbc.273.23.14620]
Maeng, S., Hunsberger, J. G., Pearson, B., Yuan, P., Wang, Y., Wei, Y., McCammon, J., Schloesser, R. J., Zhou, R., Du, J., Chen, G., McEwen, B., Reed, J. C., Manji, H. K. BAG1 plays a critical role in regulating recovery from both manic-like and depression-like behavioral impairments. Proc. Nat. Acad. Sci. 105: 8766-8771, 2008. [PubMed: 18562287] [Full Text: https://doi.org/10.1073/pnas.0803736105]
Takayama, S., Kochel, K., Irie, S., Inazawa, J., Abe, T., Sato, T., Druck, T., Huebner, K., Reed, J. C. Cloning of cDNAs encoding the human BAG1 protein and localization of the human BAG1 gene to chromosome 9p12. Genomics 35: 494-498, 1996. [PubMed: 8812483] [Full Text: https://doi.org/10.1006/geno.1996.0389]
Takayama, S., Sato, T., Krajewski, S., Kochel, K., Irie, S., Millan, J. A., Reed, J. C. Cloning and functional analysis of BAG-1: a novel Bcl-2-binding protein with anti-cell death activity. Cell 80: 279-284, 1995. [PubMed: 7834747] [Full Text: https://doi.org/10.1016/0092-8674(95)90410-7]
Wang, H.-G., Takayama, S., Rapp, U. R., Reed, J. C. Bcl-2 interacting protein, BAG-1, binds to and activates the kinase Raf-1. Proc. Nat. Acad. Sci. 93: 7063-7068, 1996. [PubMed: 8692945] [Full Text: https://doi.org/10.1073/pnas.93.14.7063]
Yang, X., Pater, A., Tang, S.-C. Cloning and characterization of the human BAG-1 gene promoter: upregulation by tumor-derived p53 mutants. Oncogene 18: 4546-4553, 1999. [PubMed: 10467399] [Full Text: https://doi.org/10.1038/sj.onc.1202843]
Zeiner, M., Gehring, U. A protein that interacts with members of the nuclear hormone receptor family: identification and cDNA cloning. Proc. Nat. Acad. Sci. 92: 11465-11469, 1995. [PubMed: 8524784] [Full Text: https://doi.org/10.1073/pnas.92.25.11465]