title: ASPP2 suppresses squamous cell carcinoma via RelA/p65-mediated repression of p63.
abstract: Squamous cell carcinoma (SCC) is highly malignant and refractory to therapy. The majority of existing mouse SCC models involve multiple gene mutations. Very few mouse models of spontaneous SCC have been generated by a single gene deletion. Here we report a haploinsufficient SCC mouse model in which exon 3 of the Tp53BP2 gene (a p53 binding protein) was deleted in one allele in a BALB/c genetic background. Tp53BP2 encodes ASPP2 (ankyrin repeats, SH3 domain and protein rich region containing protein 2). Keratinocyte differentiation induces ASPP2 and its expression is inversely correlated with p63 protein in vitro and in vivo. Up-regulation of p63 expression is required for ASPP2(Δexon3/+) BALB/c mice to develop SCC, as heterozygosity of p63 but not p53 prevents them from developing it. Mechanistically, ASPP2 inhibits ΔNp63 expression through its ability to bind IκB and enhance nuclear Rel/A p65, a component of the NF-κB transcription complex, which mediates the repression of p63. Reduced ASPP2 expression associates with tumor metastasis and increased p63 expression in human head and neck SCCs. This study identifies ASPP2 as a tumor suppressor that suppresses SCC via inflammatory signaling through NF-κB-mediated repression of p63.
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, and Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
authors.forename: Luca
authors.initials: L
authors.lastname: Tordella
authors.forename: Sofia
authors.initials: S
authors.lastname: Koch
authors.forename: Victoria
authors.initials: V
authors.lastname: Salter
authors.forename: Anna
authors.initials: A
authors.lastname: Pagotto
authors.forename: Jessica B
authors.initials: JB
authors.lastname: Doondeea
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Feller
authors.forename: Indrika
authors.initials: I
authors.lastname: Ratnayaka
authors.forename: Shan
authors.initials: S
authors.lastname: Zhong
authors.forename: Robert D
authors.initials: RD
authors.lastname: Goldin
authors.forename: Guillermina
authors.initials: G
authors.lastname: Lozano
authors.forename: Frank D
authors.initials: FD
authors.lastname: McKeon
authors.forename: Mahvash
authors.initials: M
authors.lastname: Tavassoli
authors.forename: Florian
authors.initials: F
authors.lastname: Fritzsche
authors.forename: Gerhard F
authors.initials: GF
authors.lastname: Huber
authors.forename: Matthias
authors.initials: M
authors.lastname: Rössle
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D003433:Crosses, Genetic; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D057895:Haploinsufficiency; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D008807:Mice, Inbred BALB C; D046228:Microarray Analysis; D010750:Phosphoproteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D015534:Trans-Activators / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D010750:Phosphoproteins; D034741:RNA, Small Interfering; C498144:Rela protein, mouse; D015534:Trans-Activators; D051996:Transcription Factor RelA; C511437:Trp53bp2 protein, mouse; C486419:Trp63 protein, mouse; D025521:Tumor Suppressor Proteins
keywords: T53BP2; inflammation; stratified epithelial cell tumor