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Molecular and Cellular Biology, November 2006, p. 8599-8606, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.01062-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Role of the Cyclic AMP Response Element in the bcl-2 Promoter in the Regulation of Endogenous Bcl-2 Expression and Apoptosis in Murine B Cells{triangledown}

Hong Xiang, Jinghong Wang, and Linda M. Boxer*

Center for Molecular Biology in Medicine, Veterans Affairs Palo Alto Health Care System, and Department of Medicine, Stanford University School of Medicine, Stanford, California 94305

Received 13 June 2006/ Returned for modification 16 July 2006/ Accepted 5 September 2006

We have previously shown for B-cell lines that the cyclic AMP response element (CRE) is a major positive regulatory site in the bcl-2 promoter. However, the role of the CRE in the regulation of endogenous bcl-2 expression in vivo has not been characterized. We used gene targeting to generate knock-in mice in which a mutated CRE was introduced into the bcl-2 promoter region (mutCRE-bcl2 mice). Quantitative chromatin immunoprecipitation assays revealed that mutation of the CRE abolished the binding of CREB/ATF and CBP transcription factors to the bcl-2 promoter and greatly diminished the binding of NF-{kappa}B factors. The mutant CRE significantly reduced the expression of Bcl-2 in B cells and rendered them susceptible to surface immunoglobulin- and chemotherapeutic agent-induced apoptosis. The low levels of Bcl-2 were not changed with activation of the cells. The numbers of pre-B, immature B, and mature B cells in the bone marrow were decreased, as were the numbers of splenic B cells in mutCRE-bcl2 mice. Our findings indicate that the CRE in the bcl-2 promoter has an important functional role in the regulation of endogenous Bcl-2 expression and plays a critical role in the coordination of signals that regulate B-cell survival.

* Corresponding author. Mailing address: Hematology, CCSR 1155, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA 94305-5156. Phone: (650) 849-0551. Fax: (650) 858-3982. E-mail: lboxer{at}stanford.edu.

{triangledown} Published ahead of print on 18 September 2006.

Molecular and Cellular Biology, November 2006, p. 8599-8606, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.01062-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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