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.