The deubiquitinase-encoding gene Cyld displays 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 CYLDm through K14-Cre–mediated deletion of exon 9 (hereafter refer to CyldEΔ9/Δ9). CyldEΔ9/Δ9 mice 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 in CyldEΔ9/Δ9 skin. Topical treatment with a pharmacological c-Myc inhibitor induced sebaceous and basal cell apoptosis in CyldEΔ9/Δ9 skin. Consistently, c-Myc activation was readily detected in human cylindroma and sebaceous adenoma. Taken together, our findings demonstrate that CyldEΔ9/Δ9 mice represent a disease-relevant animal model and identify TRAF6 and c-Myc as potential therapeutic targets for CYLDm-syndrome.
Yingai Jane Jin, Sally Wang, Joshua Cho, M. Angelica Selim, Tim Wright, George Mosialos, Jennifer Y. Zhang
(A) Immunoblotting of mouse skin extracts for CYLD (Ab-D1A10) and Actin. (B) IP of mouse epidermal protein extracts with an antibody against TRAF6 followed by immunoblotting with antibodies specific for K63-ubiquitin (K63-Ub) or TRAF6. The precipitated proteins, flow-through supernatants, and inputs were used for immunoblotting. (C) Clinical presentation of 1-month-old WT and CyldEΔ9/Δ9 mice. (D) Hair-length distribution. A total of 300 hairs of 2- to 3-month-old mice of each genotype were measured. (E) Clinical presentation of incisor teeth.