Dissertation/Thesis Abstract

Cowden Syndrome and PTEN Promoter Regulation Dissertation
by Teresi, Rosemary E., Ph.D., The Ohio State University, 2008, 140; 10631295
Abstract (Summary)

Germline mutations of PTEN (phosphatase and tensin homolog deleted on chromosome ten) are associated with the multi-hamartomatous disorder Cowden syndrome (CS). We show here that the PPARγ agonist Rosiglitazone, along with Lovastatin, Simvastatin, Pravastatin and Fluvastatin can induce PTEN expression by inducing PTEN transcription. Additionally, we observed, for the first time, that upregulation of SREBP protein, known to induce PPARγ expression, can increase PTEN expression. Our results indicate that Rosiglitazone, and SREBP utilizes PPARγ's transcriptional activity to induce PTEN transcription, while the statins signal through PPARγ's protein activity to upregulate PTEN expression. Studing the full-length PTEN identified a region between -854 and -791 that binds an as yet unidentified transcription factor, through which the statins induce PTEN expression.

We examined the downstream effect of five PTEN promoter variants (-861G/T, -853C/G, -834C/T, -798G/C, and -764G/A) that are not within any known cis-acting regulatory elements. We demonstrated that protein binding to the PTEN promoter (-893 to -755) was not altered in the five variants, when compared to the wild-type (WT) promoter. However, three of the variants (-861G/T, -853C/G, and -764G/A) demonstrated ~50% decrease in luciferase activity compared to the WT construct. PTEN mRNA levels were not altered in these variants, while secondary structure predictions indicated that different PTEN 5'UTR transcript folding patterns exist in three variants, suggesting an inhibition of protein translation. This was confirmed by PTEN protein analysis. These data indicate that variants causing large mRNA secondary structure alterations result in an inhibition of protein translation and a decrease in PTEN protein expression. These data emphasize the importance of PTEN promoter nucleotide variations and their ability to lead to CS progression by a novel regulatory mechanism. Importantly, these patients have a high prevalence of breast, thyroid and endometrial malignancies, thus understanding of the mechanism of PTEN dysfunction in these patients will lead to more sensitive molecular diagnostic and predictive testing and ultimately, to rational targeted therapies to treat or prevent malignancy.

Indexing (document details)
Advisor: Yates, Allen, Eng, Charis
Commitee: Chen, Ching-Shih, Guttridge, Denis, Plass, Christoph, Ringel, Matthew, Waite, Kristin
School: The Ohio State University
Department: Integrated Biomedical Science
School Location: United States -- Ohio
Source: DAI-B 78/11(E), Dissertation Abstracts International
Subjects: Biomedical engineering
Keywords: Cowden syndrome, Germline mutations
Publication Number: 10631295
ISBN: 9780355015560
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