CYLD negatively regulates cell-cycle progression by inactivating HDAC6 and increasing the levels of acetylated tubulin
Open Access
- 5 November 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 29 (1), 131-144
- https://doi.org/10.1038/emboj.2009.317
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‐κB signalling. Here we show that CYLD controls cell growth and division at the G1/S‐phase as well as cytokinesis by associating with α‐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 α‐tubulin around the nucleus. This facilitates the interaction of CYLD with Bcl‐3, leading to a significant delay in the G1‐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.Keywords
This publication has 48 references indexed in Scilit:
- Down-regulation of CYLD expression by Snail promotes tumor progression in malignant melanomaThe Journal of Experimental Medicine, 2009
- Histone Deacetylase 6 Regulates Growth Factor-Induced Actin Remodeling and EndocytosisMolecular and Cellular Biology, 2007
- The deacetylase HDAC6 is a novel critical component of stress granules involved in the stress responseGenes & Development, 2007
- HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregatesGenes & Development, 2007
- The tumor suppressor CYLD regulates entry into mitosisProceedings of the National Academy of Sciences of the United States of America, 2007
- Lymphocyte Chemotaxis Is Regulated by Histone Deacetylase 6, Independently of Its Deacetylase ActivityMolecular Biology of the Cell, 2006
- HDAC6–p97/VCP controlled polyubiquitin chain turnoverThe EMBO Journal, 2006
- Characterization of the two catalytic domains in histone deacetylase 6Biochemical and Biophysical Research Communications, 2006
- The appearance of acetylated α-tubulin during early development and cellular differentiation in XenopusDevelopmental Biology, 1989
- Acetylated α-tubulin in microtubules during mouse fertilization and early developmentDevelopmental Biology, 1988