title: Repression of Wnt/β-catenin response elements by p63 (TP63).
abstract: Submitted: TP63 (p63), a member of the tumor suppressor TP53 (p53) gene family, is expressed in keratinocyte stem cells and well-differentiated squamous cell carcinomas to maintain cellular potential for growth and differentiation. Controversially, activation of the Wnt/β-catenin signaling by p63 (Patturajan M. et al., 2002, Cancer Cells) and inhibition of the target gene expression (Drewelus I. et al., 2010, Cell Cycle) have been reported. Upon p63 RNA-silencing in squamous cell carcinoma (SCC) lines, a few Wnt target gene expression substantially increased, while several target genes moderately decreased. Although ΔNp63α, the most abundant isoform of p63, appeared to interact with protein phosphatase PP2A, neither GSK-3β phosphorylation nor β-catenin nuclear localization was altered by the loss of p63. As reported earlier, ΔNp63α enhanced β-catenin-dependent luc gene expression from pGL3-OT having 3 artificial Wnt response elements (WREs). However, this activation was detectable only in HEK293 cells examined so far, and involved a p53 family-related sequence 5' to the WREs. In Wnt3-expressing SAOS-2 cells, ΔNp63α rather strongly inhibited transcription of pGL3-OT. Importantly, ΔNp63α repressed WREs isolated from the regulatory regions of MMP7. ΔNp63α-TCF4 association occurred in their soluble forms in the nucleus. Furthermore, p63 and TCF4 coexisted at a WRE of MMP7 on the chromatin, where β-catenin recruitment was attenuated. The combined results indicate that ΔNp63α serves as a repressor that regulates β-catenin-mediated gene expression.
authors.affiliation: a Center for Medical Education and Sciences, Faculty of Medicine, University of Yamanashi , Chuo , Yamanashi , Japan.|b Oral Health Science Research Center, Kanagawa Dental University , Yokosuka , Japan.
authors.forename: Iyoko
authors.initials: I
authors.lastname: Katoh
authors.affiliation: c Medical Research Institute, Tokyo Medical and Dental University , Tokyo , Japan.
authors.forename: Nahoko
authors.initials: N
authors.lastname: Fukunishi
authors.affiliation: d Department of Cell Biology , Kyoto Pharmaceutical University , Yamashina , Kyoto , Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fujimuro
authors.affiliation: e Department of Microbiology , Faculty of Medicine, University of Yamanashi , Chuo , Yamanashi , Japan.
authors.forename: Hirotake
authors.initials: H
authors.lastname: Kasai
authors.affiliation: e Department of Microbiology , Faculty of Medicine, University of Yamanashi , Chuo , Yamanashi , Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Moriishi
authors.affiliation: b Oral Health Science Research Center, Kanagawa Dental University , Yokosuka , Japan.
authors.forename: Ryu-Ichiro
authors.initials: R
authors.lastname: Hata
authors.affiliation: b Oral Health Science Research Center, Kanagawa Dental University , Yokosuka , Japan.|c Medical Research Institute, Tokyo Medical and Dental University , Tokyo , Japan.
authors.forename: Shun-Ichi
authors.initials: S
authors.lastname: Kurata
mesh_terms: D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D001665:Binding Sites; D051177:Catenins / Q000502:physiology; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism; D020218:Response Elements; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D051153:Wnt Proteins / Q000502:physiology; D060449:Wnt Signaling Pathway
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051177:Catenins; D002843:Chromatin; C532096:TCF4 protein, human; C115051:TP63 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; C517189:PPP2CA protein, human; D054648:Protein Phosphatase 2; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7
keywords: TCF4; TP63; Wnt; p63; β-catenin