Tumor Suppressor Function of CYLD in Nonmelanoma Skin Cancer
Catalytic inactive mutant form of CYLD promotes development of squamous cell carcinoma. Keratinocyte stimulation with DMBA, TPA, or UV-B causes ubiquitination-mediated signaling and activation of JNK, NF-κB pathways, and the upregulation of VEGF gene expression. Wild-type CYLD (CYLD WT) by interaction and deubiquitination of its specific substrate blocks the propagation of downstream signaling pathways. The mutant form of CYLD (CYLD Mut), which binds to the substrate, is unable to remove K63-polyubiquitin chains from the target protein and blocks the downstream signaling pathways. In addition, the mutant form of CYLD competes with the wild-type CYLD for the same binding site on the substrate. Constitutive activation of JNK and NF-κB signaling in CYLD mutant cells (CYLD Mut), leads to development of squamous cell carcinoma (SCC).