Adenovirus-mediated gene transfer of MMAC1/PTEN to glioblastoma cells inhibits S phase entry by the recruitment of p27(Kip1) into cyclin E/CDK2 complexes

Genetic alterations in the MMAC1 tumor suppressor gene (also referred to as PTEN or TEP1) occur in several types of human cancers including glioblasto ma. Growth suppression induced hy overexpression of MMAC1 in cells with mut ant MMAC1 alleles is thought to be mediated by the inhibition of signaling through the phosphatidylinositol 3-kinase pathway, However, the exact bioch emical mechanisms by which MMAC1 exerts its growth-inhibitory effects are s till unknown. Here we report that recombinant adenovirus-mediated overexpre ssion of MMAC1 in three different MMAC1-mutant glioblastoma cell lines bloc ked progression from G(0)/G(1) to S phase of the cell cycle, Cell cycle arr est correlated with the recruitment of the cyclin-dependent kinase (CDK) in hibitor, p27(Kip1), to cyclin E immunocomplexes, which resulted in a reduct ion in CDK2 kinase activities and a decrease in levels of endogenous phosph orylated retinoblastoma protein, CDK4 kinase activities were unaffected, as were the levels of the CDK inhibitor p21(Cip1) present in cyclin E immunoc omplexes, Therefore, overexpression of MMAC1 via adenovirus-mediated gene t ransfer suppresses tumor cell growth through cell cycle inhibitory mechanis ms, and as such, represents a potential therapeutic approach to treating gl ioblastomas.