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Updated: Jul 15, 2026
Studying Cell Cycle-regulated Gene Expression by Two Complementary Cell Synchronization Protocols
Published on: June 6, 2017
The tumor suppressor CYLD regulates entry into mitosis
Frank Stegmeier1, Mathew E Sowa, Grzegorz Nalepa
1Department of Genetics, Harvard Medical School, Center for Genetics and Genomics, Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA 02115, USA.
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 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.
Insights
Mutations in the cylindromatosis (CYLD) gene cause benign tumors. CYLD regulates both apoptosis and mitosis, suggesting dual roles in tumor suppression and promotion, explaining cylindroma
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Mutations in the cylindromatosis (CYLD) gene are linked to benign cylindroma tumors.
- CYLD encodes a deubiquitinating enzyme inhibiting the NF-kappaB pathway, impacting apoptosis resistance.
- The precise tumor-suppressing mechanisms of CYLD beyond apoptosis regulation remain unclear.
Purpose of the Study:
- To investigate the role of CYLD in cell cycle regulation, specifically mitotic entry.
- To explore potential novel functions of CYLD in tumorigenesis.
- To understand the implications of CYLD's functions for the benign nature of cylindromas.
Main Methods:
- Localization studies of CYLD protein during the cell cycle.
- Analysis of CYLD protein levels during mitosis.
- Identification of interacting proteins, such as Plk1, using loss-of-function and overexpression assays.
Main Results:
- CYLD is essential for timely entry into mitosis and localizes to microtubules and the midbody.
- CYLD protein levels decrease upon exiting mitosis.
- Physical interaction and similar phenotypic effects were observed between CYLD and Plk1, suggesting Plk1 as a target.
Conclusions:
- CYLD plays a critical role in regulating mitotic entry, in addition to its known function in apoptosis regulation.
- CYLD exhibits dual functions: tumor suppression via apoptosis regulation and potential tumor promotion by enhancing mitotic entry.
- This dual role may explain the benign characteristics of cylindroma lesions.
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