title: 1α, 25-Dihydroxyvitamin D₃ and the vitamin D receptor regulates ΔNp63α levels and keratinocyte proliferation.
abstract: 1α, 25-dihydroxyvitamin D3 (VD3), a secosteriod that has been explored as an anti-cancer agent, was also shown to promote cell survival. Its receptor, the Vitamin D Receptor (VDR), is a direct target of the proto-oncogene ΔNp63α, which is overexpressed in non-melanoma skin cancers. The interconnection between VDR/VD3 signaling and ΔNp63α, led us to examine whether VDR/VD3 signaling promotes keratinocyte proliferation by regulating ΔNp63α levels. Our data demonstrate that VDR regulates ΔNp63α expression at both the transcript and protein level. Interestingly, although low doses of VD3 led to an increase in ΔNp63α protein levels and keratinocyte proliferation, high doses of VD3 failed to increase ΔNp63α protein levels and resulted in reduced proliferation. Increased expression of ΔNp63α by low dose VD3 was shown to be dependent on VDR and critical for the proliferative effects of VD3. VD3-mediated increases in ΔNp63α protein levels occur via activation of both p38 MAPK and Akt kinases. Finally, analysis of samples from patients with squamous cell carcinoma (SCC), basal cell carcinoma and precursors to invasive SCC demonstrated a significant correlation between p63 and VDR levels when compared with healthy normal skin control samples. Delineation of the mechanisms by which VD3 exerts its effect on ΔNp63α and cell proliferation is critical for determining the future of VD3 in cancer therapies.
authors.affiliation: Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Highway, Dayton, OH, USA.
authors.forename: N T
authors.initials: NT
authors.lastname: Hill
authors.affiliation: Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Highway, Dayton, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Highway, Dayton, OH, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Leonard
authors.affiliation: 1] Lifespan Health Research Center, Department of Community Health, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Highway, Dayton, OH, USA [2] Department of Pediatrics, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Highway, Dayton, OH, USA.
authors.forename: M
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Dermatology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Highway, Dayton, OH, USA.
authors.forename: H N
authors.initials: HN
authors.lastname: Shamma
authors.affiliation: Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Highway, Dayton, OH, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kadakia
mesh_terms: D002280:Basal Cell Carcinoma / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002762:Cholecalciferol / Q000494:pharmacology*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015603:Keratinocytes / Q000378:metabolism*; D009281:Naphthalenes / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D010671:Phenylurea Compounds
chemical_list: D002762:Cholecalciferol; D006575:Heterocyclic Compounds, 3-Ring; D007093:Imidazoles; D009281:Naphthalenes; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt; D011720:Pyrazoles; D011725:Pyridines; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C000715470:MAS1 protein, human; C548887:MK 2206; C115051:TP63 protein, human; C579457:VDR protein, human; C452139:doramapimod; D010671:Phenylurea Compounds; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole