title: ΔNp63α represses nuclear translocation of PTEN by inhibition of NEDD4-1 in keratinocytes.
abstract: ΔNp63α 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 ΔNp63α mediates the nuclear exclusion of PTEN. We demonstrate here that ΔNp63α 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 ΔNp63α 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 ΔNp63α. In vivo examination of normal skin demonstrated that ΔNp63α 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 ΔNp63α-mediated suppression of nuclear PTEN in basal layer keratinocytes occurs through repression of NEDD4-1.
authors.affiliation: Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, 122 Diggs Laboratory, 3640 Colonel Glenn Highway, Dayton, OH, 45435, USA.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Leonard
authors.forename: Natasha T
authors.initials: NT
authors.lastname: Hill
authors.forename: Ethan D
authors.initials: ED
authors.lastname: Grant
authors.forename: Madhavi P
authors.initials: MP
authors.lastname: Kadakia
mesh_terms: D021581:Active Transport, Cell Nucleus; D002460:Cell Line; D049109:Cell Proliferation; D015536:Down-Regulation; D056827:Endosomal Sorting Complexes Required for Transport / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D000075702:Nedd4 Ubiquitin Protein Ligases; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; D044767:Ubiquitin-Protein Ligases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human