Open AccessThe tumor suppressor CYLD regulates entry into mitosis
Author(s) -
Frank Stegmeier,
Mathew E. Sowa,
Grzegorz Nalepa,
Steven P. Gygi,
J. Wade Harper,
Stephen J. Elledge
Publication year - 2007
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0703268104
Subject(s) - mitosis , microbiology and biotechnology , plk1 , midbody , biology , carcinogenesis , centrosome , cell cycle , cytokinesis , tumor suppressor gene , ubiquitin , cancer research , gene , cell division , genetics , cell
Mutations in the cylindromatosis (CYLD ) gene cause benign tumors of skin appendages, referred to as cylindromas. TheCYLD 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 isCYLD 's only or predominant tumor-suppressing function. Here, we show thatCYLD 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 ofCYLD 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 ofCYLD could provide an explanation for the benign nature of most cylindroma lesions.