PTEN Mutation: Many Birds with One Stone in Tumorigenesis

The PTEN (phosphatase and tensin homolog deleted on chromosome ten) tumor suppressor gene is mutatedinawiderangeofmalignanciesandrecentstudies have demonstrated that PTEN prevents tumorigenesis throughmultiplemechanisms.PTENfunctionsasaplasma- membrane lipid phosphatase that antagonizes the PI3K (phosphoinositide3kinase)-AKTpathway.PTENphysically and genetically interacts with the central genome guardian p53. PTEN also associates with the centromeric protein CENP-C to maintain centromere integrity and suppresses chromosomal instability from DNA double-strand breaks (DSBs) through transcriptional regulation of Rad51 (radiosensitive yeast mutant 51). Moreover PTEN controls the growth and proliferation of haematopoietic stem cells (HSC) and restrains cells from leukemia in an mTOR (mammalian target of rapamycin) dependent manner.Thus, restoring PTEN functions in cancer cells directly or indirectlyholdsgreatpromiseforcancertherapy. PTEN (phosphatase and tensin homolog deleted on chromosome ten) was first identified as a tumor suppressor gene in 1997 (1). PTEN is mutated in a wide range of malignancies, especially solid tumors and it is, second only to p53, the most frequently affected tumor suppressor in human carcinomas. Somatic mutations of PTEN occur in multiple sporadic malignancies while germline mutations of PTEN lead to inherited hamartoma and Cowden syndrome (2).Importantly,PTEN ishaploinsufficientbecauseasingle copy was unable to prevent prostate cancer either in combination with the loss of certain other tumor suppressor genes or with genetically engineered reduction of PTEN expression just below heterozygosity (3-7). PTENisamultiple-domainpolypeptideof403aminoacids. Itcontainsanamino-terminalphosphatasedomainhomologous to chicken tensin and a C2 domain, which mediates the association of signal proteins to plasma membranes. The C- terminal PDZ (PSD95, DlgA and Zo-1) domain-binding sequence and PEST (rich in proline, glutamate, serine, and threonine residues) domain regulate protein stability via the ubiquitin-proteasome pathway (2). PTEN has two canonical PEST domains, which is a signature in many short-lived proteins degraded by the ubiquitin pathway. Given that the proteinlevelofPTENishighlycorrelatedwithcarcinogenesis inawiderangeofcancercases,itshouldbetightlycontrolled. Indeed,PTENisregulatedbyubiquitin-mediatedproteasomal