Transcription factor p53 and
phosphatase PTEN are two
tumor suppressors that play essential roles in suppression of
carcinogenesis. However, the mechanisms by which p53 mediates anticancer activity and the relationship between p53 and PTEN are not well understood. In the present study, we found that pretreatment of mouse epidermal Cl41 cells with
pifithrin-alpha, an inhibitor for p53-dependent transcriptional activation, resulted in a marked increase in UV-induced activation of
activator protein 1 (AP-1) and
nuclear factor kappaB (
NF-kappaB). Consistent with activation of
AP-1 and
NF-kappaB,
pifithrin-alpha was also able to enhance the UV-induced phosphorylation of c-Jun-NH2-kinases (JNK) and p38
kinase, whereas it did not show any effect on phosphorylation of
extracellular signal-regulated kinases. Furthermore, the UV-induced signal activation, including phosphorylation of JNK, p38
kinase, Akt, and
p70S6K, was significantly enhanced in p53-deficient cells (p53-/-), which can be reversed by p53 reconstitution. In addition, knockdown of p53 expression by its
small interfering RNA also caused the elevation of
AP-1 activation and Akt phosphorylation induced by UV radiation. These results show that p53 has a suppressive activity on the cell signaling pathways leading to activation of
AP-1 and
NF-kappaB in cell response to UV radiation. More importantly, deficiency of p53 expression resulted in a decrease in
PTEN protein expression, suggesting that p53 plays a critical role in the regulation of PTEN expression. In addition, overexpression of wild-type PTEN resulted in inhibition of UV-induced
AP-1 activity. Because PTEN is a well-known
phosphatase involved in the regulation of
phosphatidylinositol 3-kinase (PI-3K)/Akt signaling pathway, taken together with the evidence that PI-3K/Akt plays an important role in the activation of
AP-1 and
NF-kappaB during
tumor development, we anticipate that inhibition of
AP-1 and
NF-kappaB by
tumor suppressor p53 seems to be mediated via PTEN, which may be a novel mechanism involved in anticancer activity of p53
protein.