The bcl-2 gene is a blocker of programmed cell death, whose expression becomes dysregulated in a large proportion of human cancers, including adenocarcinomas of the breast, prostate, and colon, squamous carcinomas of the lung, and lymphomas and leukemias. Over-production of the Bcl-2 protein has been shown to make tumor cells strikingly more resistant to cell death induced by nearly all chemotherapeutic drugs and radiation, suggesting that bcl-2 can in some ways be viewed as a multidrug- resistance gene. The product of the bcl-2 gene is an integral membrane protein that resides in the outer mitochondrial membrane, nuclear envelope, and endoplasmic reticulum. The predicted amino-acid sequence of this protein however has failed to suggest a biochemical mechanism of action. To gain further insights into Bcl-2 mechanisms, an interaction cloning technique was used to identify cDNAs that encode Bcl-2 binding proteins, leading to the discovery of a novel protein, BAG-1. Recombinant BAG-1 protein was shown by several methods to specifically bind to Bcl-2 in vitro, and the two proteins could be co-immunoprecipitated from mammalian cells. Immunomicroscopy suggests that BAG-1 and Bcl-2 may reside at least in part in the same subcellular locations. Co-transfection of BAG- 1 and Bcl-2-encoding expression plasmids results in enhanced suppression of apoptosis compared to either BAG-1 or Bcl-2 alone. The human BAG-1 gene maps to chromosome 9p13, a region possibly involved in hereditary syndromes that suggest a defect in developmental cell death. A comprehensive investigation of the structure, expression, and function of the BAG-1 gene is proposed, including determination of (i) the exon/intron organization of the human and mouse BAG-1 genes; (ii) the subcellular location of the BAG-1 protein and its in vivo patterns of production; (iii) the specific sites where BAG-1 binds to Bcl-2 and the importance of this interaction for Bcl-2 function; (iv) the biochemical properties of the BAG-1 protein; (v) the in vivo function of BAG-1 through creation of transgenic and knock-out mice; and (vi) the possibility of alterations in BAG-1 in cancers and hereditary syndromes mapped to 9p13.
| Maeng, Sungho; Hunsberger, Joshua G; Pearson, Brandon et al. (2008) BAG1 plays a critical role in regulating recovery from both manic-like and depression-like behavioral impairments. Proc Natl Acad Sci U S A 105:8766-71 |
| Iwasaki, Masahiro; Homma, Sachiko; Hishiya, Akinori et al. (2007) BAG3 regulates motility and adhesion of epithelial cancer cells. Cancer Res 67:10252-9 |
| Dohm, Christoph P; Siedenberg, Sandra; Liman, Jan et al. (2006) Bax inhibitor-1 protects neurons from oxygen-glucose deprivation. J Mol Neurosci 29:1-8 |
| Homma, Sachiko; Iwasaki, Masahiro; Shelton, G Diane et al. (2006) BAG3 deficiency results in fulminant myopathy and early lethality. Am J Pathol 169:761-73 |
| Fukushima, Toru; Zapata, Juan M; Singha, Netai C et al. (2006) Critical function for SIP, a ubiquitin E3 ligase component of the beta-catenin degradation pathway, for thymocyte development and G1 checkpoint. Immunity 24:29-39 |
| Krajewska, Maryla; Turner, Bruce C; Shabaik, Ahmed et al. (2006) Expression of BAG-1 protein correlates with aggressive behavior of prostate cancers. Prostate 66:801-10 |
| Liman, Jan; Ganesan, Sundar; Dohm, Christoph P et al. (2005) Interaction of BAG1 and Hsp70 mediates neuroprotectivity and increases chaperone activity. Mol Cell Biol 25:3715-25 |
| Gotz, Rudolf; Wiese, Stefan; Takayama, Shinichi et al. (2005) Bag1 is essential for differentiation and survival of hematopoietic and neuronal cells. Nat Neurosci 8:1169-78 |
| Pusztai, Lajos; Krishnamurti, Savitri; Perez Cardona, Jorge et al. (2004) Expression of BAG-1 and BcL-2 proteins before and after neoadjuvant chemotherapy of locally advanced breast cancer. Cancer Invest 22:248-56 |
| Kermer, Pawel; Digicaylioglu, Murat H; Kaul, Marcus et al. (2003) BAG1 over-expression in brain protects against stroke. Brain Pathol 13:495-506 |
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