title: Epidermal CYLD inactivation sensitizes mice to the development of sebaceous and basaloid skin tumors.
abstract: The deubiquitinase-encoding geneCylddisplays a dominant genetic linkage to a wide spectrum of skin-appendage tumors, which could be collectively designated as CYLD mutant-syndrome (CYLDm-syndrome). Despite recent advances, little is understood about the molecular mechanisms responsible for this painful and difficult-to-treat skin disease. Here, we generated a conditional mouse model with epidermis-targeted expression of a catalytically deficient CYLDmthrough K14-Cre-mediated deletion of exon 9 (hereafter refer toCyldEΔ9/Δ9).CyldEΔ9/Δ9mice were born alive but developed hair and sebaceous gland abnormalities and dental defects at 100% and 60% penetrance, respectively. Upon topical challenge with DMBA/TPA, these animals primarily developed sebaceous and basaloid tumors resembling human CYLDm-syndrome as opposed to papilloma, which is most commonly induced in WT mice by this treatment. Molecular analysis revealed that TRAF6-K63-Ubiquitination (K63-Ub), c-Myc-K63-Ub, and phospho-c-Myc (S62) were markedly elevated inCyldEΔ9/Δ9skin. Topical treatment with a pharmacological c-Myc inhibitor induced sebaceous and basal cell apoptosis inCyldEΔ9/Δ9skin. Consistently, c-Myc activation was readily detected in human cylindroma and sebaceous adenoma. Taken together, our findings demonstrate thatCyldEΔ9/Δ9mice represent a disease-relevant animal model and identify TRAF6 and c-Myc as potential therapeutic targets for CYLDm-syndrome.
authors.affiliation: Department of Dermatology, Duke University, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Yingai Jane
authors.initials: YJ
authors.lastname: Jin
authors.affiliation: Department of Dermatology, Duke University, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Sally
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Dermatology, Duke University, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Cho
authors.affiliation: Department of Pathology, Duke University, Durham, North Carolina, USA.
authors.forename: M Angelica
authors.initials: MA
authors.lastname: Selim
authors.affiliation: Dental School, University North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Wright
authors.affiliation: School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Mosialos
authors.affiliation: Department of Dermatology, Duke University, Duke University Medical Center, Durham, North Carolina, USA; Department of Pathology, Duke University, Durham, North Carolina, USA.
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Zhang