There has been intense investigation regarding the interaction between the
phosphatase and
tensin homologue deleted on chromosome 10 (PTEN) and p53
tumor suppressors. p53 has been shown to up-regulate PTEN expression as a transcriptional activator. However, clinical observations by immunohistochemistry studies indicate that significant increases in p53
protein levels coexist with reduced or absent expression of
PTEN protein in a variety of
neoplasias. In this study, we propose a mechanism that begins to explain how p53 can both up-regulate and down-regulate PTEN. We have found that
PTEN protein is down-regulated under
proteasome dysfunction induced by
proteasome inhibitor MG132 in both human lymphoblast cells and MCF7 cells. The reduction of PTEN is coincident with elevated p53
protein levels and the association between PTEN and p53 but independent of its
phosphatase activities. Quantitative reverse transcription-PCR indicates that
proteasome inhibition does not reduce PTEN message levels but affects
PTEN protein stability. The p53 inhibitor,
pifithrin-alpha, is able to attenuate the effect of
proteasome inhibition. Using ectopic expression studies in p53-null mouse embryonic fibroblasts and p53/PTEN-null PC3 cells, we show that PTEN is more stable in p53-null cells compared with p53-expressing cells. Inhibition of
caspases, the downstream targets of p53, particularly
caspase-3, can partially restore the stability of PTEN. This study provides the first evidence that p53 is able to down-regulate
PTEN protein stability in stressed cells. Our study sheds some light on the mechanisms that regulate
PTEN protein stability, which is important to fully elucidate to comprehend the broad neoplastic manifestations of
Cowden syndrome/Bannayan-Riley-Ruvalcaba and sporadic
cancers.