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USP44 regulates centrosome positioning to prevent aneuploidy and suppress tumorigenesis
Ying Zhang, … , Jan van Deursen, Paul J. Galardy
Ying Zhang, … , Jan van Deursen, Paul J. Galardy
Published November 26, 2012
Citation Information: J Clin Invest. 2012;122(12):4362-4374. https://doi.org/10.1172/JCI63084.
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Research Article Article has an altmetric score of 11

USP44 regulates centrosome positioning to prevent aneuploidy and suppress tumorigenesis

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Abstract

Most human tumors have abnormal numbers of chromosomes, a condition known as aneuploidy. The mitotic checkpoint is an important mechanism that prevents aneuploidy by restraining the activity of the anaphase-promoting complex (APC). The deubiquitinase USP44 was identified as a key regulator of APC activation; however, the physiological importance of USP44 and its impact on cancer biology are unknown. To clarify the role of USP44 in mitosis, we engineered a mouse lacking Usp44. We found that USP44 regulated the mitotic checkpoint and prevented chromosome lagging. Mice lacking Usp44 were prone to the development of spontaneous tumors, particularly in the lungs. Additionally, USP44 was frequently downregulated in human lung cancer, and low expression correlated with a poor prognosis. USP44 inhibited chromosome segregation errors independent of its role in the mitotic checkpoint by regulating centrosome separation, positioning, and mitotic spindle geometry. These functions required direct binding to the centriole protein centrin. Our data reveal a new role for the ubiquitin system in mitotic spindle regulation and underscore the importance of USP44 in the pathogenesis of human cancer.

Authors

Ying Zhang, Oded Foreman, Dennis A. Wigle, Farhad Kosari, George Vasmatzis, Jeffrey L. Salisbury, Jan van Deursen, Paul J. Galardy

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Figure 3

Correction of the checkpoint defect in Usp44-null cells does not prevent mitotic errors.

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Correction of the checkpoint defect in Usp44-null cells does not prevent...
(A) MEFs of the indicated genotype were transduced with H2B-YFP, followed by live-cell microscopy. Mitotic arrest duration was determined by calculating the time from nuclear envelope breakdown (NEBD) to chromosome decondensation. Graph represents the mean percentage ± SEM of cells remaining in mitosis at each time point (3 lines per genotype). Total n = 50–90 cells for each genotype per condition. (B) The interval between NEBD and anaphase was determined in the absence of nocodazole for MEFs of the indicated genotypes. The graph represents the cumulative incidence of anaphase at each time point (mean ± SEM of 3 lines). Total n = 50–60 cells for each genotype. (C) Experimental scheme for D and E. MEFs expressing H2B-YFP were marked in prophase and followed by time-lapse microscopy to determine mitotic duration and chromosome mis-segregation. Two hours after the addition of proTAME, new prophase cells were selected and similarly examined. (D) Duration of mitosis for Usp44+/+, Usp44–/–, and Mad2l1+/– MEFs imaged before and after proTAME addition. The graph represents the mean ± SEM for 3 lines per genotype. Total n = 25–35 cells per time period. (E) The effect of proTAME on chromosome mis-segregation in Usp44+/+ (n = 67 before, 83 after), Usp44–/– (n = 65 cells per time period from 3 MEF lines), and Mad2l1+/– MEFs (n = 20–25 cells per time period, 1 MEF line). The patterned area indicates the proportion of cells encountering at least one lagging chromosome. The graph represents the mean ± SEM. *P < 0.05, 2-way ANOVA.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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