Potential regulation of PTEN phosphatase by PP2A and set proteins and its role in oral cancer predisposition

Abstract

Cancer is the second-highest rate of mortality in Brazil and is still responsible for a high number of deaths worldwide. During tumorigenesis, several changes occur in the genome, transcriptome, proteome, and interatome, these alterations allow the development of the malignant cell. There are described alterations in signaling of PI3K-Akt pathway, such as gain of function of the kinase PI3K or loss of function of PTEN phosphatase, leading to increased PtdIns(3,4,5)P3 with constitutive activation of downstream targets like Akt kinase. The negative regulation of Akt can be performed by the phosphatase PP2A, which is inhibited by the SET protein (or inhibitor 2 of PP2A). Many mechanisms may contribute to deregulation of cell signaling, and the increase in the amount of a single protein can lead to unbalance in the process. Recently, our group identified the increase of SET protein in various samples of oral carcinoma, which was associated with activation of Akt. Therefore, the objective of this work is to characterize the potential mechanisms of regulation of protein phosphatase PTEN by PP2A and SET and its involvement in predisposition to oral carcinoma. Some of the strategies that will be used are interference RNA, overexpression of regulatory proteins, changes in DNA methylation as control of transcription, analysis of microRNAs and mRNAs by real time PCR and electrophoresis, co-immunoprecipitation, both in vitro model with cultured cellular lines and in transgenic animal model. (AU)