Novel Mechanisms of PTEN Gene Regulation

Grants and Contracts Details


The pro-apoptotic tumor suppressor gene PTEN (Phospatase and Tensin Homologue deleted from Chromosome 10) is a negative regulator of the PI-3 kinase/Akt dependent cell survival pathway. PTEN is located on chromosome 10q23 within a region that shows loss of heterozygosity in many human cancers, and PTEN gene function is lost in diverse cancers either by mutation of PTEN or deletion of chromosome 10q23. However, in several cancers such as non-small cell lung cancer and thyroid cancer, the PTEN gene is intact and wild type, but its expression is diminished. As haplo-insufficiency of PTEN is associated with tumorigenesis, understanding the mechanism(s) involved in epigenetic down-regulation of PTEN is of both clinical and fundamental significance. Recent studies have shown that the PTEN pseudo-gene but not wild type PTEN gene is methylated, indicatingthat DNAmethylationis not a potential mechanism for silencing of the PTENpromoter leading to diminishedPTENgene expression. Our preliminary studies indicated that the anti-apoptotictranscriptional regulatorNF-kappaBand oncogenic Ras, which are over-expressedand activated in lung cancer, down-regulatethe expressionof PTEN. Interestingly,oncogenic Ras up-regulates the expression of the transcription factor Egr-1,which by itself suppressesPTENgene expression. The studies proposed here will address the mechanisms for down-regulation of PTEN gene expression that are functionally relevant; i.e., they result in elevated phospho-Akt levels and anti-a poptosis. We will determine the mechanisms of suppression of PTEN gene expression by NF-kappaB (Aim 1), and by oncogenic Ras (Aim 2) that confer apoptosis inhibition, tumor progression and chemo- or radiation-resistance. Because these studies will elucidate novel mechanisms of PTEN tumor suppressor gene regulation by pro-survival and oncogenic factors most commonly encountered in lung cancer, the findings may lead to the development of intervention strategies that can ablate the NF-kappaB or activated Ras-inducible anti-apoptotic pathways and thereby restore expression and the pro-apoptotic potential of PTEN. PERFORMANCE SITE(S) (organization, city, state) University of Kentucky, Lexington, KY KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required infonnation in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name Organization Role on Project Rangnekar, Vivek M. Burikhanov, Ravshan University of Kentucky University of Kentucky University of Kentucky PI Zhou, Yanming Research Associate Research Associate Disclosure Permission Statement ADolicabieto SBIRISTTR OnlY. See instructions. D Yes DNa PHS 398 (Rev. 05/01) Page_2- Form Page 2
Effective start/end date2/5/041/31/10


  • National Cancer Institute: $1,471,182.00


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