title: ΔNp63α regulates keratinocyte proliferation by controlling PTEN expression and localization.
abstract: ΔNp63α, 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 ΔNp63α regulates PTEN expression. Knockdown of ΔNp63α led to increases in PTEN levels and loss of activated Akt, while overexpression of ΔNp63α decreased PTEN levels and elevated active Akt. The repression of PTEN by ΔNp63α occurs independently of p53 status, as loss of ΔNp63α increases PTEN expression in cell lines with and without functional p53. In addition, decreased levels of ΔNp63α resulted in an increase in nuclear PTEN. Conversely, in vivo nuclear PTEN was absent in the proliferative basal layer of the epidermis where ΔNp63α expression is highest. Additionally, we show that in keratinocytes a balance between ΔNp63α and PTEN regulates Akt activation and maintains normal proliferation rates. This balance is disrupted in non-melanoma skin cancers through increased ΔNp63α levels, and could enhance proliferation and subsequent neoplastic development. Our studies show that ΔNp63α negatively regulates PTEN, thereby providing a feedback loop between PTEN, Akt and ΔNp63α, which has an integral role in skin cancer development.
authors.affiliation: Department of Biochemistry and Molecular Biology, Wright State University, Colonel Glenn Highway, Dayton, OH 45435, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Leonard
authors.forename: R
authors.initials: R
authors.lastname: Kommagani
authors.forename: V
authors.initials: V
authors.lastname: Payal
authors.forename: L D
authors.initials: LD
authors.lastname: Mayo
authors.forename: H N
authors.initials: HN
authors.lastname: Shamma
authors.forename: M P
authors.initials: MP
authors.lastname: Kadakia
mesh_terms: D000818:Animals; D001483:Base Sequence; D002280:Basal Cell Carcinoma / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation; D004789:Enzyme Activation; D025461:Feedback, Physiological; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020218:Response Elements; D012867:Skin / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human