Dissecting the effects of PTEN on tumour formation and gene expression

Abstract

The PI3K/PTEN signalling pathway plays an important role in regulation of cell growth, survival, metabolism and migration in many different types of cells. Aberrations in this pathway have implications in metabolic and hyper proliferative disorders such as diabetes and cancer. PTEN is a tumour suppressor found mutated in many primary and metastatic human cancers. It has lipid and protein phosphatase activities, which are both required to inhibit cellular invasion and mediate most of its largest effects on gene expression. PTEN can antagonize the PI3K/AKT pathway by dephosphorylating phosphatidylinositol 3,4,5 trisphosphate (PIP3) thereby acting as tumour suppressor. Most of PTEN’s tumour suppressor activities have been attributed to its ability to regulate signalling downstream of AKT. However, our recent data in glioma cells have shown that two PTEN mutants, PTEN Y138L and PTEN R308C, can regulate AKT phosphorylation and signalling downstream but fail to regulate processes such as cell invasion and epithelial cell architecture. These findings suggest that in some circumstances the regulation not of AKT, but of signalling mechanisms that control invasion can correlate with PTEN-mediated tumour suppression. In order to understand how PTEN could regulate tumorigenesis, two new transgenic knock in mice lines were developed expressing Pten Y138L and Pten R308C mutants. The Y138L mutation is embryonic lethal and homozygous embryos die at day 9.5 of pregnancy. Interestingly, heterozygous PTEN Y138L mice develop tumour as early as 5 months and about half develop tumours before 18 months of age. R308C heterozygous and homozygous mice are both viable instead, but data suggest that the mutation may also be tumorigenic. Furthermore, to understand how PTEN WT and PTEN Y138L could regulate gene expression, I performed luciferase promoter reporter assays. From these first experiments, significant effects of PTEN WT or PTEN Y138L on gene expression were not detected. Together, these studies help us understand how PTEN suppresses tumour formation in vivo and regulate gene expression.