The tumor suppressor CYLD regulates entry into mitosis

Frank Stegmeier, Mathew E. Sowa, Grzegorz Nalepa, Steven P. Gygi, J. Wade Harper, Stephen J. Elledge

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

Mutations in the cylindromatosis (CYLD) gene cause benign tumors of skin appendages, referred to as cylindromas. The CYLD gene encodes a deubiquitinating enzyme that removes Lys-63-linked ubiquitin chains from IκB kinase signaling components and thereby inhibits NF-κB pathway activation. The dysregulation of NF-κB activity has been proposed to promote cell transformation in part by increasing apoptosis resistance, but it is not clear whether this is CYLD's only or predominant tumor-suppressing function. Here, we show that CYLD is also required for timely entry into mitosis. Consistent with a cell-cycle regulatory function, CYLD localizes to microtubules in interphase and the midbody during telophase, and its protein levels decrease as cells exit from mitosis. We identified the protein kinase Plk1 as a potential target of CYLD in the regulation of mitotic entry, based on their physical interaction and similar loss-of-function and overexpression phenotypes. Our findings raise the possibility that, as with other genes regulating tumorigenesis, CYLD has not only tumor-suppressing (apoptosis regulation) but also tumor-promoting activities (enhancer of mitotic entry). We propose that this additional function of CYLD could provide an explanation for the benign nature of most cylindroma lesions.

Original languageEnglish (US)
Pages (from-to)8869-8874
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number21
DOIs
StatePublished - May 22 2007
Externally publishedYes

Fingerprint

Mitosis
Adenoid Cystic Carcinoma
Neoplasms
Apoptosis
Telophase
Genes
Interphase
Ubiquitin
Microtubules
Protein Kinases
Cell Cycle
Carcinogenesis
Phosphotransferases
Phenotype
Skin
Mutation
Proteins

Keywords

  • Cell cycle
  • Mitotic entry
  • Plk1
  • siRNA screen

ASJC Scopus subject areas

  • General
  • Genetics

Cite this

Stegmeier, F., Sowa, M. E., Nalepa, G., Gygi, S. P., Harper, J. W., & Elledge, S. J. (2007). The tumor suppressor CYLD regulates entry into mitosis. Proceedings of the National Academy of Sciences of the United States of America, 104(21), 8869-8874. https://doi.org/10.1073/pnas.0703268104

The tumor suppressor CYLD regulates entry into mitosis. / Stegmeier, Frank; Sowa, Mathew E.; Nalepa, Grzegorz; Gygi, Steven P.; Harper, J. Wade; Elledge, Stephen J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 21, 22.05.2007, p. 8869-8874.

Research output: Contribution to journalArticle

Stegmeier, F, Sowa, ME, Nalepa, G, Gygi, SP, Harper, JW & Elledge, SJ 2007, 'The tumor suppressor CYLD regulates entry into mitosis', Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 21, pp. 8869-8874. https://doi.org/10.1073/pnas.0703268104
Stegmeier, Frank ; Sowa, Mathew E. ; Nalepa, Grzegorz ; Gygi, Steven P. ; Harper, J. Wade ; Elledge, Stephen J. / The tumor suppressor CYLD regulates entry into mitosis. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 21. pp. 8869-8874.
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