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J. Biol. Chem., Vol. 279, Issue 16, 15916-15928, April 16, 2004

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An Evolutionary and Molecular Analysis of Bmp2 Expression^*

Kevin L. Abrams, Junwang Xu, Celine Nativelle-Serpentini, Shabnam Dabirshahsahebi, and Melissa B. Rogers¶

From the Department of Biology, University of South Florida, Tampa, Florida 33620 and the Department of Biochemistry and Molecular Biology, UMDNJ, New Jersey Medical School, Newark, New Jersey 07101-1709

The coding regions of many metazoan genes are highly similar. For example, homologs to the key developmental factor bone morphogenetic protein (BMP) 2 have been cloned by sequence identity from arthropods, mollusks, cnidarians, and nematodes. Wide conservation of protein sequences suggests that differential gene expression explains many of the vast morphological differences between species. To test the hypothesis that the regulatory mechanisms controlling this evolutionarily ancient and critical gene are conserved, we compared sequences flanking Bmp2 genes of several species. We identified numerous conserved noncoding sequences including some retained because the fish lineage separated 450 million years ago. We tested the function of some of these sequences in the F9 cell model system of Bmp2 expression. We demonstrated that both mouse and primate Bmp2 promoters drive a reporter gene in an expression pattern resembling that of the endogenous transcript in F9 cells. A conserved Sp1 site contributes to the retinoic acid responsiveness of the Bmp2 promoter, which lacks a classical retinoic acid response element. We have also discovered a sequence downstream of the stop codon whose conservation between humans, rodents, deer, chickens, frogs, and fish is striking. A fragment containing this region influences reporter gene expression in F9 cells. The conserved region contains elements that may mediate the half-life of the Bmp2 transcript. Together, our molecular and evolutionary analysis has identified new regulatory elements controlling Bmp2 expression.

Received for publication, December 10, 2003

^* This work was supported in part by the Molecular Imaging and Molecular Biology Core Facilities at the H. Lee Moffitt Cancer Center and Research Institute, the Molecular Resource Facility at the UMDNJ, National Institute of Child Health and Human Development Grant HD31117 (to M. B. R.), and American Heart Association Predoctoral Fellowship 0010110B (to K. L. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Biochemistry & Molecular Biology (MSB E627), UMDNJ, New Jersey Medical School, P.O. Box 1709, Newark, NJ 07101-1709. Tel.: 973-972-2984; Fax: 973-972-5594; E-mail: rogersmb{at}umdnj.edu.

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