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Smurf2 as a novel mitotic regulator: From the spindle assembly checkpoint to tumorigenesis

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Title: Smurf2 as a novel mitotic regulator: From the spindle assembly checkpoint to tumorigenesis
Author(s): Osmundson, Evan C.; Ray, Dipankar; Moore, Finola E.; Kiyokawa, Hiroaki
Subject(s): mitosis Smurf2
Abstract: The execution of the mitotic program with high fidelity is dependent upon precise spatiotemporal regulation of posttranslational protein modifications. For example, the timely polyubiquitination of critical mitotic regulators by Anaphase Promoting Complex/Cyclosome (APC/C) is essential for the metaphase to anaphase transition and mitotic exit. The spindle assembly checkpoint prevents unscheduled activity of APC/C-Cdc20 in early mitosis, allowing bipolar attachment of kinetochores to mitotic spindle and facilitating equal segregation of sister chromatids. The critical effector of the spindle checkpoint, Mitotic arrest deficient 2 (Mad2), is recruited to unattached kinetochores forming a complex with other regulatory proteins to efficiently and cooperatively inhibit APC/C-Cdc20. A weakened and/or dysfunctional spindle checkpoint has been linked to the development of genomic instability in both cell culture and animal models, and evidence suggests that aberrant regulation of the spindle checkpoint plays a critical role in human carcinogenesis. Recent studies have illuminated a network of both degradative and non-degradative ubiquitination events that regulate the metaphase to anaphase transition and mitotic exit. Within this context, our recent work showed that the HECT (Homologous to E6-AP C-terminus)-family E3 ligase Smurf2 (Smad specific ubiquitin regulatory factor 2), known as a negative regulator of transforming growth factor-beta (TGF-beta) signaling, is required for a functional spindle checkpoint by promoting the functional localization and stability of Mad2. Here we discuss putative models explaining the role of Smurf2 as a new regulator in the spindle checkpoint. The dynamic mitotic localization of Smurf2 to the centrosome and other critical mitotic structures provides implications about mitotic checkpoint control dependent on various ubiquitination events. Finally, deregulated Smurf2 activity may contribute to carcinogenesis by perturbed mitotic control.
Issue Date: 2009-07-07
Publisher: BioMed Central
Citation Info: Osmundson, E. C., Ray, D., Moore, F. E., & Kiyokawa, H. 2009. Smurf2 as a novel mitotic regulator: From the spindle assembly checkpoint to tumorigenesis. Cell Division, 4. DOI: 10.1186/1747-1028-4-14
Type: Article
Description: The original source is available through BioMed Central at DOI: 10.1186/1747-1028-4-14. © 2009 Osmundson et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
URI: http://hdl.handle.net/10027/7708
ISSN: 1747-1028
Sponsor: Research in Kiyokawa laboratory has been supported in part by the National Institutes of Health (CA112282, CA100204, and HD38085), H-Foundation, Searle Leadership Fund and Zell Fund.
Date Available in INDIGO: 2011-05-27
 

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