PMID:23187126

Citation	Zhang, Y, Foreman, O, Wigle, DA, Kosari, F, Vasmatzis, G, Salisbury, JL, van Deursen, J and Galardy, PJ (2012) USP44 regulates centrosome positioning to prevent aneuploidy and suppress tumorigenesis. J. Clin. Invest. 122:4362-74
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.
Links	PubMed PMC3533537 Online version:10.1172/JCI63084
Keywords	Abnormal Karyotype; Adenocarcinoma/genetics; Adenocarcinoma/metabolism; Aneuploidy; Animals; Calcium-Binding Proteins/metabolism; Cell Cycle Checkpoints; Cell Transformation, Neoplastic/genetics; Cells, Cultured; Centrosome/metabolism; Chromosome Segregation; Endopeptidases/genetics; Endopeptidases/metabolism; Endopeptidases/physiology; Genes, Tumor Suppressor; Genomic Instability; Humans; Lung Neoplasms/genetics; Lung Neoplasms/metabolism; Mice; Mice, Knockout; Mitotic Spindle Apparatus/metabolism; Tumor Suppressor Proteins/genetics; Tumor Suppressor Proteins/metabolism; Tumor Suppressor Proteins/physiology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:UBP44		GO:0007059: chromosome segregation	ECO:0000315:		P		see figures 1 and 2 to see how the protein is the one to help with chromosome segregation	complete CACAO 7392
MOUSE:UBP44	involved_in	GO:0007059: chromosome segregation	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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