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Molecular and Cellular Biology, July 1999, p. 4582-4591, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Dominant Negative Murine Serum Response Factor: Alternative Splicing within the Activation Domain Inhibits Transactivation of Serum Response Factor Binding Targets

Narasimhaswamy S. Belaguli,1 Wei Zhou,1 Thuy-Hanh T. Trinh,1 Mark W. Majesky,1,2 and Robert J. Schwartz1,*

Departments of Cell Biology1 and Pathology,2 Baylor College of Medicine, Houston, Texas 77030

Received 30 December 1998/Returned for modification 3 April 1999/Accepted 9 April 1999

Primary transcripts encoding the MADS box superfamily of proteins, such as MEF2 in animals and ZEMa in plants, are alternatively spliced, producing several isoformic species. We show here that murine serum response factor (SRF) primary RNA transcripts are alternatively spliced at the fifth exon, deleting approximately one-third of the C-terminal activation domain. Among the different muscle types examined, visceral smooth muscles have a very low ratio of SRFDelta 5 to SRF. Increased levels of SRFDelta 5 correlates well with reduced smooth muscle contractile gene activity within the elastic aortic arch, suggesting important biological roles for differential expression of SRFDelta 5 variant relative to wild-type SRF. SRFDelta 5 forms DNA binding-competent homodimers and heterodimers. SRFDelta 5 acts as a naturally occurring dominant negative regulatory mutant that blocks SRF-dependent skeletal alpha -actin, cardiac alpha -actin, smooth alpha -actin, SM22alpha , and SRF promoter-luciferase reporter activities. Expression of SRFDelta 5 interferes with differentiation of myogenic C2C12 cells and the appearance of skeletal alpha -actin and myogenin mRNAs. SRFDelta 5 repressed the serum-induced activity of the c-fos serum response element. SRFDelta 5 fused to the yeast Gal4 DNA binding domain displayed low transcriptional activity, which was complemented by overexpression of the coactivator ATF6. These results indicate that the absence of exon 5 might be bypassed through recruitment of transcription factors that interact with extra-exon 5 regions in the transcriptional activating domain. The novel alternatively spliced isoform of SRF, SRFDelta 5, may play an important regulatory role in modulating SRF-dependent gene expression.

* Corresponding author. Mailing address: Department of Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-6649. Fax: (713) 798-7799. E-mail: schwartz{at}bcm.tmc.edu.

Molecular and Cellular Biology, July 1999, p. 4582-4591, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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