Transcriptional activation of p21WAF1by PTEN/MMAC1 tumr suppressor

The recently discovered tumor suppressor gene PTEN has been found mutated i n many types of advanced tumors. When introduced into tumor cells that lack the wild-type allele of the gene, PTEN was able to suppress the growth of these cells. Here, we have analyzed how PTEN might alter cell cycle-regulat ory controls to achieve this growth-inhibitory effect. We found that overex pression of PTEN stimulates the synthesis of three inhibitors of cyclin-dep endent kinases, p21(WAF1), p27(KIP1), and p57(KIP2). This effect is very sp ecific, as the expression of other components of the cell cycle engine, var ious cyclins and cyclin-dependent kinases, is not affected. For p21(WAF1) w e show that this induction is due to the p53-independent transcriptional ac tivation of its promoter. In addition, increased expression of PTEN rendere d the cells more sensitive to apoptotic cell death. Therefore, our data sug gest a two-fold mechanism of growth inhibition by PTEN: one that acts via t he increased expression of CKIs such as p21(WAF1), and another that augment s the cellular propensity for apoptotic cell death.