?Np63? regulates keratinocyte proliferation by controlling PTEN expression and localization.

ABSTRACT: ?Np63?, implicated as an oncogene, is upregulated by activated Akt, part of a well-known cell survival pathway. Inhibition of Akt activation by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and the presence of putative p63-binding sites in the pten promoter led us to investigate whether ?Np63? regulates PTEN expression. Knockdown of ?Np63? led to increases in PTEN levels and loss of activated Akt, while overexpression of ?Np63? decreased PTEN levels and elevated active Akt. The repression of PTEN by ?Np63? occurs independently of p53 status, as loss of ?Np63? increases PTEN expression in cell lines with and without functional p53. In addition, decreased levels of ?Np63? resulted in an increase in nuclear PTEN. Conversely, in vivo nuclear PTEN was absent in the proliferative basal layer of the epidermis where ?Np63? expression is highest. Additionally, we show that in keratinocytes a balance between ?Np63? and PTEN regulates Akt activation and maintains normal proliferation rates. This balance is disrupted in non-melanoma skin cancers through increased ?Np63? levels, and could enhance proliferation and subsequent neoplastic development. Our studies show that ?Np63? negatively regulates PTEN, thereby providing a feedback loop between PTEN, Akt and ?Np63?, which has an integral role in skin cancer development.

SUBMITTER: Leonard MK 

PROVIDER: S-EPMC3214913 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature