Human Molecular Genetics Advance Access published online on March 6, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm053
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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
1 Genomic Medicine Institute, Cleveland, Ohio, USA 2 Lerner Research Institute, Cleveland, Ohio, USA 3 Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio, USA 4 Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA 5 CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
Correspondence and request for reprints to: Charis Eng, MD, PhD, Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, NE-50, Cleveland, Ohio 44195, USA Tel.: +1 216 444 3440 Fax: +1 216 636 0655 Email: engc{at}ccf.org
Received February 4, 2007; Revised February 4, 2007; Accepted February 28, 2007
Germline mutations in PTEN, encoding a phosphatase on 10q23, are 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 basepairs (bp) upstream of the PTEN core promoter and more than 1.1 kilobasepairs (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 4, 3 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.
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