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J. Biol. Chem., Vol. 276, Issue 27, 25589-25597, July 6, 2001

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A Novel Bipartite Intronic Splicing Enhancer Promotes the Inclusion of a Mini-exon in the AMP Deaminase 1 Gene^*

Thomas Genetta, Hiroko Morisaki^§¶, Takayuki Morisaki^§, and Edward W. Holmes^**

From the  Joseph P. Stokes Research Institute, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, the ^§ Department of Bioscience, National Cardiovascular Center Research Institute, Suita, Osaka 565-0871, Japan, and the  School of Medicine, University of California at San Diego, La Jolla, California 92093-0602

Alternative splicing of the 12-base exon 2 of the adenosine monophosphate deaminase (AMPD) gene is subject to regulation by both cis- and trans-regulatory signals. The extent of exon 2 inclusion is stage- and cell type-specific and is subject to the physiological state of the cell. In adult skeletal muscle, a cell type that regulates the activity of this allosteric enzyme at several levels, the exon 2-plus form of AMPD, predominates. We have performed a systematic analysis of the cis-acting regulatory sequences that reside in the intron immediately downstream of this mini-exon. A complex element comprising sequences that enhance exon 2 inclusion and sequences that counteract this effect resides in the middle of this intron. We demonstrate that the enhancing component is bipartite, with more than a kilobase of sequence separating the two functional sites. The presence of even minimal levels the mini-exon in the fully processed AMPD mRNA requires both of these sites, neither of which appears in any other published splicing enhancer. An RNA binding activity derived from a muscle cell line requires both of the enhancing sites. Mutations in either of the sites that eliminate exon 2 inclusion abrogate this binding activity.

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