title: Novel CARD11 Mutations in Human Cutaneous Squamous Cell Carcinoma Lead to Aberrant NF-κB Regulation.
abstract: NF-κB signaling plays a crucial role in regulating proliferation and differentiation in the epidermis. Alterations in the NF-κB pathway can lead to skin pathologies with a significant burden to human health such as psoriasis and cutaneous squamous cell carcinoma (cSCC). Caspase recruitment domain (CARD)-containing scaffold proteins are key regulators of NF-κB signaling by providing a link between membrane receptors and NF-κB transcriptional subunits. Mutations in the CARD family member, CARD14, have been identified in patients with the inflammatory skin diseases psoriasis and pityriasis rubra pilaris. Here, we describe that the gene coding for another CARD scaffold protein, CARD11, is mutated in more than 38% of 111 cSCCs, and show that novel variants outside of the coiled-coil domain lead to constitutively activated NF-κB signaling. CARD11 protein expression was detectable in normal skin and increased in all cSCCs tested. CARD11 mRNA levels were comparable with CARD14 in normal skin and CARD11 mRNA was increased in cSCC. In addition, we identified CARD11 mutations in peritumoral and sun-exposed skin, suggesting that CARD11-mediated alterations in NF-κB signaling may be an early event in the development of cSCC.
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, United Kingdom.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Watt
authors.affiliation: Centre for Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Karin J
authors.initials: KJ
authors.lastname: Purdie
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, United Kingdom.
authors.forename: Nicoline Y
authors.initials: NY
authors.lastname: den Breems
authors.affiliation: Department of Dermatology, University of California, San Francisco, California.
authors.forename: Michelle
authors.initials: M
authors.lastname: Dimon
authors.affiliation: Department of Dermatology, University of California, San Francisco, California.
authors.forename: Sarah T
authors.initials: ST
authors.lastname: Arron
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, United Kingdom.
authors.forename: Angela T
authors.initials: AT
authors.lastname: McHugh
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, United Kingdom.
authors.forename: Dylan J
authors.initials: DJ
authors.lastname: Xue
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, United Kingdom.
authors.forename: Jasbani H S
authors.initials: JH
authors.lastname: Dayal
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, United Kingdom.
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Proby
authors.affiliation: Centre for Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Harwood
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, United Kingdom; Centre for Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Leigh
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, United Kingdom; Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Electronic address: andrew.south@jefferson.edu.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: South
mesh_terms: D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D002478:Cells, Cultured; D004817:Epidermis / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006162:Guanylate Cyclase / Q000235:genetics*; D006801:Humans; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D018307:Neoplasms, Squamous Cell / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D053468:CARD Signaling Adaptor Proteins; D016328:NF-kappa B; C426242:CARD11 protein, human; D006162:Guanylate Cyclase