Journal Article

Comparative genomic and functional analyses reveal a novel <i>cis</i>-acting <i>PTEN</i> regulatory element as a highly conserved functional E-box motif deleted in Cowden syndrome

Marcus G. Pezzolesi, Kevin M. Zbuk, Kristin A. Waite and Charis Eng

in Human Molecular Genetics

Volume 16, issue 9, pages 1058-1071
Published in print May 2007 | ISSN: 0964-6906
Published online March 2007 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddm053
Comparative genomic and functional analyses reveal a novel cis-acting PTEN regulatory element as a highly conserved functional E-box motif deleted in Cowden syndrome

Show Summary Details

Preview

Germline mutations in PTEN, encoding a phosphatase on 10q23, cause Cowden syndrome (CS) and Bannayan–Riley–Ruvalcaba syndrome (BRRS). Approximately, 10% of CS-related PTEN mutations occur in the PTEN promoter and 11% of BRRS-related mutations include large deletions, often favoring the gene's 5′ end (exon 1, promoter). In order to better understand the mechanism(s) underlying the deregulation of PTEN in these syndromes, it is important that functional cis-regulatory elements be identified. We employed a comparative genomic approach combined with molecular genetic techniques to identify a highly conserved sequence upstream of the PTEN promoter, sharing 80% sequence identity among Homo sapiens, Mus musculus and Rattus norvegicus. Within this region, we identified a canonical E-box sequence (CACGTG) located at position −2181 to −2176, approximately 800 bp upstream of the PTEN core promoter and more than 1.1 kb upstream of its minimal promoter region (located at –958 to –821). In vitro assays suggest that this motif is recognized by members of the basic region-helix-loop-helix-leucine-zipper (bHLH-LZ) transcription factor family, USF1 and USF2, and reporter assays indicate that this novel E-box is involved in mediating PTEN transcriptional activation. Four of 30 CS/CS-like patients, without previously identified PTEN mutations, were found with germline deletions of the E-box element. Of the four, three had deletions stretching to exon 1, but not 3′ of it; importantly, one classic CS patient harbored a germline deletion localizing to this E-box region, further affirming the role of this element in PTEN's regulation and deregulation, and its contribution to the pathogenesis of CS.

Journal Article.  8469 words.  Illustrated.

Subjects: Genetics and Genomics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.