title: Elevated ΔNp63α Levels Facilitate Epidermal and Biliary Oncogenic Transformation.
abstract: Unlike its family member p53, TP63 is rarely mutated in human cancer. However, ΔNp63α protein levels are often elevated in tumors of epithelial origin, such as squamous cell carcinoma and cholangiocarcinoma. To study the oncogenic properties of ΔNp63α in vivo, we generated transgenic mice overexpressing ΔNp63α from the Rosa26 locus promoter controlled by keratin 5-Cre. We found that these mice spontaneously develop epidermal cysts and ectopic ΔNp63α expression in the bile duct epithelium that leads to dilatation of the intrahepatic biliary ducts, to hepatic cyst formation and bile duct adenoma. Moreover, when subjected to models of 7,12-dimethylbenz[a]anthracene-based carcinogenesis, tumor initiation was increased in ΔNp63α transgenic mice in a gene dosage-dependent manner although ΔNp63α overexpression did not alter the sensitivity to 7,12-dimethylbenz[a]anthracene-induced cytotoxicity in vivo. However, keratinocytes isolated from ΔNp63α transgenic mice displayed increased survival and delayed cellular senescence compared with wild-type keratinocytes, marked by decreased p16Ink4aand p19Arfexpression. Taken together, we show that increased ΔNp63α protein levels facilitate oncogenic transformation in the epidermis as well as in the bile duct.
authors.affiliation: Molecular Signaling and Cell Death Unit, Inflammation Research Center, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Michael
authors.initials: M
authors.lastname: Devos
authors.affiliation: Molecular Signaling and Cell Death Unit, Inflammation Research Center, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Barbara
authors.initials: B
authors.lastname: Gilbert
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Molecular and Cellular Oncology Unit, Inflammation Research Center, VIB, Ghent, Belgium.
authors.forename: Geertrui
authors.initials: G
authors.lastname: Denecker
authors.affiliation: Molecular Signaling and Cell Death Unit, Inflammation Research Center, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Leurs
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Molecular Signal Transduction in Inflammation Unit, Inflammation Research Center, VIB, Ghent, Belgium.
authors.forename: Conor
authors.initials: C
authors.lastname: Mc Guire
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Inflammation Research Center, VIB, Ghent, Belgium.
authors.forename: Kelly
authors.initials: K
authors.lastname: Lemeire
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Transgenic mice core facility, VIB, Ghent, Belgium.
authors.forename: Tino
authors.initials: T
authors.lastname: Hochepied
authors.affiliation: GNOMIXX bvba, Statistics for Genomics, Ghent, Belgium.
authors.forename: Marnik
authors.initials: M
authors.lastname: Vuylsteke
authors.affiliation: Department of Dermatology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Jo
authors.initials: J
authors.lastname: Lambert
authors.affiliation: Department of Pathology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Caroline
authors.initials: C
authors.lastname: Van Den Broecke
authors.affiliation: Department of Pathology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Louis
authors.initials: L
authors.lastname: Libbrecht
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Vascular Cell Biology Unit, Department for Molecular Biomedical Research, VIB, Ghent, Belgium.
authors.forename: Jody
authors.initials: J
authors.lastname: Haigh
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Molecular and Cellular Oncology Unit, Inflammation Research Center, VIB, Ghent, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Berx
authors.affiliation: Molecular Signaling and Cell Death Unit, Inflammation Research Center, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Saskia
authors.initials: S
authors.lastname: Lippens
authors.affiliation: Molecular Signaling and Cell Death Unit, Inflammation Research Center, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenabeele
authors.affiliation: Molecular Signaling and Cell Death Unit, Inflammation Research Center, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. Electronic address: wim.declercq@irc.vib-UGent.be.
authors.forename: Wim
authors.initials: W
authors.lastname: Declercq
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D001650:Bile Duct Neoplasms / Q000209:etiology*; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D016922:Cellular Senescence; D006965:Hyperplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000032:analysis / Q000502:physiology*; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000209:etiology*; D013755:Tetradecanoylphorbol Acetate; D015534:Trans-Activators / Q000032:analysis / Q000502:physiology*
chemical_list: D010750:Phosphoproteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate