The tumor suppressor CYLD regulates entry into mitosis.
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 I kappa B kinase signaling components and thereby inhibits NF-kappaB pathway activation. The dysregulation of NF-kappaB 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.
Stegmeier
Frank
F
Department of Genetics, Harvard Medical School, Center for Genetics and Genomics, Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA 02115, USA.
Sowa
Mathew E
ME
Nalepa
Grzegorz
G
Gygi
Steven P
SP
Harper
J Wade
JW
Elledge
Stephen J
SJ
D000595:Amino Acid Sequence; D002460:Cell Line; D000074749:Deubiquitinating Enzyme CYLD; D005786:Gene Expression Regulation; D006801:Humans; D008938:Mitosis; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D050807:ets-Domain Protein Elk-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D016328:NF-kappa B; D025521:Tumor Suppressor Proteins; D050807:ets-Domain Protein Elk-1; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD