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Cloning and characterization of the human BAG-1 gene promoter: upregulation by tumor-derived p53 mutants

Oncogene volume 18, pages 4546–4553 (1999)Cite this article

Abstract

BAG-1 is an anti-apoptotic protein that interacts with Bcl-2, Bcl-XL, Hsp70/Hsc70, Raf-1 and numerous hormone or growth factor receptors. Recently, BAG-1 has been found to be overexpressed in a variety of human cancer cell lines and some tumors. However, the molecular mechanism of BAG-1 upregulation is still unclear. In this study, we cloned 0.9 kb of human genomic DNA, BGEV, 5′ flanking the BAG-1 open reading frame. BGEV subcloned into a promoterless luciferase reporter vector conferred high promoter activity in various human cancer cell lines. Deletion analysis of this sequence localized the region of maximal BAG-1 promoter activity from nucleotide positions −353 to −54, upstream of the first start codon CTG. Sequence analysis of the BAG-1 promoter region showed the absence of a TATA box but identified a CCAAT box, several GC boxes, a CpG island and several transcriptional factor binding sites, which may be important in the regulation of BAG-1 transcription. Most importantly, functional characterization of the BAG-1 promoter in vivo demonstrated that gain-of-function p53 mutants derived from human tumors upregulated the transcription of BAG-1 RNA and the expression of a reporter gene from the BAG-1 promoter. These results indicated that we have isolated the functional constitutive BAG-1 promoter. Furthermore, the data suggested that overexpression of BAG-1 in some tumors may be due to upregulation of the human BAG-1 promoter by mutant p53.

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Acknowledgements

We thank Y Hao and G Chernenko for excellent technical assistance and Drs B Vogelstein, KH Vousden and GP Zambetti for providing mutant p53 plasmids. The investigation was supported by grants from the Medical Research Council of Canada and a grant from the National Cancer Institute of Canada with funds from the Canadian Cancer Society.

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Authors and Affiliations

  1. Division of Basic Medical Sciences, Faculty of Medicine, Memorial University of Newfoundland, 300 Prince Philip Drive, St John's, Newfoundland, A1B 3V6, Canada

    Xiaolong Yang, Alan Pater & Shou-Ching Tang

  2. Newfoundland Cancer Treatment and Research Foundation, Dr. H. Bliss Murphy Cancer Centre, 300 Prince Philip Drive, St John's, A1B 3V6, NF, Canada

    Shou-Ching Tang

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Yang, X., Pater, A. & Tang, SC. Cloning and characterization of the human BAG-1 gene promoter: upregulation by tumor-derived p53 mutants. Oncogene 18, 4546–4553 (1999). https://doi.org/10.1038/sj.onc.1202843

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