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 Atta, Stephen C. Dahl, Gerard T. Berry, Joseph S. Handler, H. Moo Kwon

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)20615-20621
Number of pages7
JournalJournal of Biological Chemistry
Volume273
Issue number32
DOIs
StatePublished - Aug 7 1998

Fingerprint

5' Flanking Region
Inositol
Transcription
Genes
Sodium
NFATC Transcription Factors
Methylation
Cell membranes
Blood Proteins
Brain
Membrane Proteins
Transcription Factors
Salts
Cell Membrane
Tissue
Kidney
Experiments

ASJC Scopus subject areas

  • Biochemistry

Cite this

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. / Rim, Jong S.; Atta, Mohamed; Dahl, Stephen C.; Berry, Gerard T.; Handler, Joseph S.; Kwon, H. Moo.

In: Journal of Biological Chemistry, Vol. 273, No. 32, 07.08.1998, p. 20615-20621.

Research output: Contribution to journalArticle

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