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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 SRF
5 to SRF. Increased
levels of SRF
5 correlates well with reduced smooth muscle
contractile gene activity within the elastic aortic arch, suggesting
important biological roles for differential expression of SRF
5
variant relative to wild-type SRF. SRF
5 forms DNA binding-competent
homodimers and heterodimers. SRF
5 acts as a naturally occurring
dominant negative regulatory mutant that blocks SRF-dependent skeletal
-actin, cardiac
-actin, smooth
-actin, SM22
, and SRF
promoter-luciferase reporter activities. Expression of SRF
5
interferes with differentiation of myogenic C2C12 cells and the
appearance of skeletal
-actin and myogenin mRNAs. SRF
5 repressed
the serum-induced activity of the c-fos serum response
element. SRF
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,
SRF
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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