Abstract
Phosphatase and tensin homolog deleted on chromosome 10, or PTEN, is a well-characterized tumor suppressor with both lipid and protein phosphatase activities. PTEN is often downregulated by epigenetic mechanisms such as hypermethylation, which leads to constitutive activation of the PI3K–Akt pathway. Large datasets from next-generation sequencing, however, revealed that mutations in PTEN may not only hamper protein function but may also affect interactions with downstream effectors, leading to variable oncogenic readouts. Here, two novel PTEN mutations, Q171R and Y65S, identified in Filipino colorectal cancer patients, were phenotypically characterized in NIH3T3 and HCT116 cells, alongside the C124S canonical mutant and wild-type controls. The novel mutants increased cellular proliferation, resistance to apoptosis and migratory capacity. They induced gross morphological changes including cytoplasmic shrinkage, increased cellular protrusions and extensive cytoskeletal reorganization. The mutants also induced a modest increase in Akt phosphorylation. Further mechanistic studies will help determine the differential oncogenic potencies of these mutants, and resolve whether the structural constraints imposed by the mutations may have altered associations with downstream effectors.
Highlights
Phosphatase and tensin homolog deleted on chromosome 10, or PTEN, is a protein that is often mutated in a wide variety of cancers, including colorectal cancer (CRC).It functions as a regulator of the PI3K–Akt signaling pathway by dephosphorylating phosphatidylinositol (PI) 3,4,5-triphosphate to PI-4,5-bisphosphate, thereby interrupting the signaling cascade and halting function
We report the phenotypic characterization of the novel PTEN phosphatase domain mutants Q171R and Y65S identified in a retrospective study of Filipino colorectal cancer patients at the University of the Philippines National Institutes of Health [14]
To determine the possible effects of the novel PTEN mutants Q171R and Y65S on cell proliferation, NIH3T3 cells transfected with each mutant construct were seeded in tripliproliferation, NIH3T3 cells transfected with each mutant construct were seeded in triplicate cate and in equal cell numbers onto 96-well plates
Summary
Phosphatase and tensin homolog deleted on chromosome 10, or PTEN, is a protein that is often mutated in a wide variety of cancers, including colorectal cancer (CRC). It functions as a regulator of the PI3K–Akt signaling pathway by dephosphorylating phosphatidylinositol (PI) 3,4,5-triphosphate to PI-4,5-bisphosphate, thereby interrupting the signaling cascade and halting function. In the context of CRC, PTEN function has been found to be altered through both genetic and epigenetic mechanisms. Previous studies have demonstrated how deletion, point mutations, hypermethylation and altered subcellular location of PTEN are all closely correlated with carcinogenesis, disease progression, and prognosis of malignancy [2]. PTEN was shown to be subject to regulation by microRNAs, pseudogene molecular decoys, its antisense transcript PTEN-AS, and competitive endogenous RNAs [3,4,5,6,7]
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