Epidermal CYLD inactivation sensitizes mice to the development of sebaceous and basaloid skin tumors
Yingai Jane Jin, … , George Mosialos, Jennifer Y. Zhang
Yingai Jane Jin, … , George Mosialos, Jennifer Y. Zhang
Published July 21, 2016
Citation Information: JCI Insight. 2016;1(11):e86548. https://doi.org/10.1172/jci.insight.86548.
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Research Article Dermatology Development

Epidermal CYLD inactivation sensitizes mice to the development of sebaceous and basaloid skin tumors

Abstract

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.

Authors

Yingai Jane Jin, Sally Wang, Joshua Cho, M. Angelica Selim, Tim Wright, George Mosialos, Jennifer Y. Zhang

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Figure 6

Working model for Cyld regulation of ectodermal appendages.

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Working model for Cyld regulation of ectodermal appendages. Growth facto...
Growth factors such as EGF and cytokines such as TNFα increase K63-Ub of TRAF6 and c-Myc, as well as TRAF6 downstream NF-κB signaling. NF-κB transcriptionally induces Cyld, which in turn inhibits TRAF6/NF-κB and c-Myc. In cells with homozygous Cyld mutation, the catalytically deficient CYLDm protein exerts dominant negative effects on K63-Ub deubiquitination of its substrates and consequently uncontrolled activation of NF-κB, c-Myc, and other gene regulators. NF-κB in turn increases Cyldm gene transcription, thereby forming a positive feedback loop to promote dysregulation of sebaceous gland, hair follicle, and dental growth. In Cyld–/– cells, such dominant negative effects of Cyldm on substrates and the transcriptional feedback from NF-κB to Cyldm gene expression are absent.