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J Biol Chem, Vol. 275, Issue 5, 3168-3172, February 4, 2000
From the Dipartimento di Biologia Molecolare, Università
degli Studi di Siena via Fiorentina 1, 53100 Siena, Italy
The utrophin gene codes for a large cytoskeletal
protein closely related to dystrophin. Its transcription is driven by a
TATA-less promoter. Here we analyzed 40 kilobases of the 5' end region
of the utrophin gene searching for new utrophin regulatory elements in
muscle cells. By transient transfection of utrophin genomic fragments
in front of a reporter gene, we identified a new enhancer that maps
downstream of the transcription start site within the second intron and
co-localizes with a DNase I-hypersensitive site. By deletion analysis
it was mapped to a sequence of 128 base pairs that retains the whole
activity. Linker scanning mutagenesis showed that most of the enhancer
sequence is essential for its transcriptional activity. Binding
analysis with nuclear cell extracts demonstrated that the enhancer
regulatory elements, identified by mutagenesis, are protected from
DNase I digestion. Because utrophin can functionally substitute
dystrophin, the identification and characterization of new regulatory
elements provide new targets for possible therapies of Duchenne
muscular dystrophy aiming at the up-regulation of the utrophin
expression in muscle cells.
Utrophin Transcription Is Activated by an Intronic Enhancer*
*
This work was supported by Italian Telethon Project 970 and
by Italian PNR.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Fax: 39-0577-234929;
E-mail: oliviero@unisi.it.
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