PTEN (phosphatase and tensin homologue, deleted on chromosome 10) is a tumor suppressor with dual phosphatase activity and mutations of its gene, PTEN, have been associated with many sporadic cancers and heritable neoplasia syndromes, including Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. However, accumulating evidence now shows that PTEN may have novel functions other than as a phosphatase. In the present study, we show that PTEN is able to autoregulate its expression through the stabilization of another tumor suppressor p53. We further show that PTEN enhances p53 transactivation, a relationship that requires the interaction between PTEN and p53 and is PTEN phosphatase independent. We show that cell lines from Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients with germ line PTEN promoter mutations in the vicinity of the p53-binding motifs have altered p53 regulation. This seems to be due to reduced PTEN stability and decreased PTEN-p53 interactions. Our data provide clues to better understand the regulation of PTEN expression and the possible mechanisms of the pathogenesis of the subset of Cowden syndrome individuals with germ line promoter variation and who lack mutations in the PTEN coding region and splice sites. Importantly, this mechanism also holds for those sporadic tumors that lack intragenic mutations but have hemizygous deletion of PTEN, which includes the promoter region as manifested by loss-of-heterozygosity of 10q markers. The importance of our observations is underlined by the broad spectrum of neoplasias that harbor somatic PTEN or p53 alterations, or both.