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Cowden Syndrome and PTEN Promoter Regulation

Teresi, Rosemary E.
http://rave.ohiolink.edu/etdc/view?acc_num=osu1206109150

Abstract Details

2008, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science.
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 PPAR-gamma 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 PPAR-gamma expression, can increase PTEN expression. Our results indicate that Rosiglitazone, and SREBP utilizes PPAR-gamma's transcriptional activity to induce PTEN transcription, while the statins signal through PPAR-gamma'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.
Allen Yates, MD, PhD (Advisor)
Charis Eng, MD, PhD (Advisor)
Kristin Waite, PhD (Committee Member)
Ching-Shih Chen, PhD (Committee Member)
Denis Guttridge, PhD (Committee Member)
Matthew Ringel, MD, PhD (Committee Member)
Christoph Plass, PhD (Committee Member)
140 p.
Biomedical Research

Recommended Citations

Citations

  • Teresi, R. E. (2008). Cowden Syndrome and PTEN Promoter Regulation [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1206109150

    APA Style (7th edition)

  • Teresi, Rosemary. Cowden Syndrome and PTEN Promoter Regulation. 2008. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1206109150.

    MLA Style (8th edition)

  • Teresi, Rosemary. "Cowden Syndrome and PTEN Promoter Regulation." Doctoral dissertation, Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1206109150

    Chicago Manual of Style (17th edition)

osu1206109150
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© 2008, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.