DeltaNp63alpha regulates keratinocyte proliferation by controlling PTEN expression and localization.

摘要

DeltaNp63alpha, 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 DeltaNp63alpha regulates PTEN expression. Knockdown of DeltaNp63alpha led to increases in PTEN levels and loss of activated Akt, while overexpression of DeltaNp63alpha decreased PTEN levels and elevated active Akt. The repression of PTEN by DeltaNp63alpha occurs independently of p53 status, as loss of DeltaNp63alpha increases PTEN expression in cell lines with and without functional p53. In addition, decreased levels of DeltaNp63alpha resulted in an increase in nuclear PTEN. Conversely, in vivo nuclear PTEN was absent in the proliferative basal layer of the epidermis where DeltaNp63alpha expression is highest. Additionally, we show that in keratinocytes a balance between DeltaNp63alpha and PTEN regulates Akt activation and maintains normal proliferation rates. This balance is disrupted in non-melanoma skin cancers through increased DeltaNp63alpha levels, and could enhance proliferation and subsequent neoplastic development. Our studies show that DeltaNp63alpha negatively regulates PTEN, thereby providing a feedback loop between PTEN, Akt and DeltaNp63alpha, which has an integral role in skin cancer development.