ΔNp63α represses nuclear translocation of PTEN by inhibition of NEDD4-1 in keratinocytes

Delta Np63 alpha maintains the proliferative potential of keratinocytes by inhibiting the transcription and nuclear localization of the tumor suppressor PTEN as shown earlier by our laboratory. The goal of this study was to define the mechanisms by which Delta Np63 alpha mediates the nuclear exclusion of PTEN. We demonstrate here that Delta Np63 alpha reduces the ubiquitination of PTEN, a key signaling event in the nuclear translocation of PTEN. The decrease in ubiquitinated PTEN correlated with the ability of Delta Np63 alpha to bind to neuronal precursor developmentally down regulated 4 (NEDD4) promoter and transcriptionally repress the E3 ubiquitin ligase NEDD4-1. Knockdown of NEDD4-1 in cultured keratinocytes was sufficient to attenuate the increase in nuclear PTEN observed upon silencing of Delta Np63 alpha. In vivo examination of normal skin demonstrated that Delta Np63 alpha and NEDD4-1 were both expressed in the basal layer of the epidermis and this correlated with nuclear exclusion of PTEN. Altogether, these studies suggest that Delta Np63 alpha-mediated suppression of nuclear PTEN in basal layer keratinocytes occurs through repression of NEDD4-1.