CYLD negatively regulates cell-cycle progression by inactivating HDAC6 and increasing the levels of acetylated tubulin.

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.
Mesh Terms:
Acetylation, Animals, Carcinoma, Adenoid Cystic, Catalytic Domain, Cell Cycle, Cell Line, Tumor, Cytokinesis, Genes, Tumor Suppressor, Histone Deacetylases, Humans, Keratinocytes, Melanocytes, Melanoma, Mice, Microtubules, Mutation, Recombinant Fusion Proteins, Skin Neoplasms, Tetradecanoylphorbol Acetate, Tubulin, Tumor Suppressor Proteins
EMBO J.
Date: Jan. 06, 2010
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