Abstract
CYLD is a tumour-suppressor gene that is mutated in a benign skin tumour syndrome called cylindromatosis. The CYLD gene product is a deubiquitinating enzyme that was shown to regulate cell proliferation, cell survival and inflammatory responses, mainly through inhibiting NF-kappaB signalling. Here we show that CYLD controls cell growth and division at the G(1)/S-phase as well as cytokinesis by associating with alpha-tubulin and microtubules through its CAP-Gly domains. Translocation of activated CYLD to the perinuclear region of the cell is achieved by an inhibitory interaction of CYLD with histone deacetylase-6 (HDAC6) leading to an increase in the levels of acetylated alpha-tubulin around the nucleus. This facilitates the interaction of CYLD with Bcl-3, leading to a significant delay in the G(1)-to-S-phase transition. Finally, CYLD also interacts with HDAC6 in the midbody where it regulates the rate of cytokinesis in a deubiquitinase-independent manner. Altogether these results identify a mechanism by which CYLD regulates cell proliferation at distinct cell-cycle phases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Animals
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Carcinoma, Adenoid Cystic / genetics
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Carcinoma, Adenoid Cystic / metabolism
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Carcinoma, Adenoid Cystic / pathology
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Catalytic Domain
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Cell Cycle / genetics
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Cell Cycle / physiology*
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Cell Line, Tumor
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Cytokinesis
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Deubiquitinating Enzyme CYLD
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Genes, Tumor Suppressor
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Histone Deacetylase 6
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Histone Deacetylases / chemistry
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Histone Deacetylases / metabolism*
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Humans
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Keratinocytes / cytology
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Keratinocytes / drug effects
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Keratinocytes / metabolism
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Melanocytes / cytology
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Melanocytes / drug effects
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Melanocytes / metabolism
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Melanoma / genetics
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Melanoma / metabolism
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Melanoma / pathology
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Mice
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Microtubules / metabolism
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Mutation
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Skin Neoplasms / genetics
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Skin Neoplasms / metabolism
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Skin Neoplasms / pathology
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Tetradecanoylphorbol Acetate / pharmacology
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Tubulin / chemistry
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Tubulin / metabolism*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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Recombinant Fusion Proteins
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Tubulin
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Tumor Suppressor Proteins
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CYLD protein, human
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Deubiquitinating Enzyme CYLD
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HDAC6 protein, human
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Histone Deacetylase 6
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Histone Deacetylases
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Tetradecanoylphorbol Acetate