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J Biol Chem, Vol. 273, Issue 32, 20615-20621, August 7, 1998
Transcription of the Sodium/myo-Inositol
Cotransporter Gene Is Regulated by Multiple Tonicity-responsive
Enhancers Spread over 50 Kilobase Pairs in the 5'-Flanking Region
Jong S.
Rim ,
Mohamed G.
Atta ,
Stephen C.
Dahl ,
Gerard T.
Berry§,
Joseph S.
Handler , and
H. Moo
Kwon
From the Division of Nephrology, Johns Hopkins School
of Medicine, Baltimore, Maryland 21205 and the § Department
of Pediatrics, University of Pennsylvania School of Medicine,
Philadelphia, Pennsylvania, 19104
The sodium/myo-inositol cotransporter
is a plasma membrane protein responsible for concentrative cellular
accumulation of myo-inositol in a variety of tissues. When
cells in kidney and brain are exposed to a hyperosmolar salt condition
(hypertonicity) due to the operation of urinary concentration mechanism
and pathological conditions, respectively, they survive the stress of
hypertonicity by raising the cellular concentration of
myo-inositol. Transcription of the
sodium/myo-inositol cotransporter gene is markedly
stimulated in response to hypertonicity, leading to an increase in the
activity of the cotransporter, which in turn drives the osmoprotective accumulation of myo-inositol. To understand the molecular
mechanisms by which hypertonicity stimulates transcription, we analyzed
the 5'-flanking region of the cotransporter gene for
cis-acting regulatory sequences. We identified five
tonicity-responsive enhancers that are scattered over 50 kilobase
pairs. All the enhancers are variations of the same type of enhancer
interacting with the transcription factor named tonicity-responsive
enhancer binding protein. In vivo methylation
experiments demonstrated that exposure of cells to hypertonicity
increases the binding of tonicity-responsive enhancer binding protein
to the enhancer sites, indicating that all of these enhancers are
involved in the transcriptional stimulation. We conclude that the
sodium/myo-inositol cotransporter gene is regulated by a
large region (~50 kilobase pairs) upstream of the gene.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

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(2002)
200101339.
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Copyright © 1998 by the American Society for Biochemistry and Molecular Biology.
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