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Molecular and Cellular Biology, January 1999, p. 78-85, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Polypyrimidine Tract-Binding Protein Positively Regulates Inclusion of an Alternative 3'-Terminal Exon

Hua Lou,1,* David M. Helfman,2 Robert F. Gagel,3 and Susan M. Berget1

Verna and Marrs McLean Department of Biochemistry, Baylor College of Medicine,1 and Section of Endocrine Neoplasia and Hormonal Disorders, University of Texas, M. D. Anderson Cancer Center,3 Houston, Texas 77030, and Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 117242

Received 29 July 1998/Returned for modification 10 September 1998/Accepted 14 October 1998

Polypyrimidine tract-binding protein (PTB) is an abundant vertebrate hnRNP protein. PTB binding sites have been found within introns both upstream and downstream of alternative exons in a number of genes that are negatively controlled by the binding of PTB. We have previously reported that PTB binds to a pyrimidine tract within an RNA processing enhancer located adjacent to an alternative 3'-terminal exon within the gene coding for calcitonin and calcitonin gene-related peptide. The enhancer consists of a pyrimidine tract and CAG directly abutting on a 5' splice site sequence to form a pseudoexon. Here we show that the binding of PTB to the enhancer pyrimidine tract is functional in that exon inclusion increases when in vivo levels of PTB increase. This is the first example of positive regulation of exon inclusion by PTB. The binding of PTB was antagonistic to the binding of U2AF to the enhancer-located pyrimidine tract. Altering the enhancer pyrimidine tract to a consensus sequence for the binding of U2AF eliminated enhancement of exon inclusion in vivo and exon polyadenylation in vitro. An additional PTB binding site was identified close to the AAUAAA hexanucleotide sequence of the exon 4 poly(A) site. These observations suggest a dual role for PTB in facilitating recognition of exon 4: binding to the enhancer pyrimidine tract to interrupt productive recognition of the enhancer pseudoexon by splicing factors and interacting with the poly(A) site to positively affect polyadenylation.

* Corresponding author. Mailing address: Verna and Marrs McLean Department of Biochemistry, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-4622. Fax: (713) 795-5487. E-mail: hlou{at}bcm.tmc.edu.

Molecular and Cellular Biology, January 1999, p. 78-85, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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