BAG-1--A NOVEL BCL-2 BINDING PROTEIN

bcl-2基因是程序性细胞死亡的阻滞剂，其表达

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.