USP44 regulates centrosome positioning to prevent aneuploidy and suppress tumorigenesis.

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
Journal	The Journal of clinical investigation (J Clin Invest) Vol. 122 Issue 12 Pg. 4362-74 (Dec 2012) ISSN: 1558-8238 [Electronic] United States
PMID	23187126 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Calcium-Binding Proteins Cetn2 protein, mouse Tumor Suppressor Proteins Endopeptidases USP44 protein, mouse Ubiquitin Thiolesterase
Topics	Abnormal Karyotype Adenocarcinoma (genetics, metabolism) Adenocarcinoma of Lung Aneuploidy Animals Calcium-Binding Proteins (metabolism) Cell Cycle Checkpoints Cell Transformation, Neoplastic (genetics) Cells, Cultured Centrosome (metabolism) Chromosome Segregation Endopeptidases (genetics, metabolism, physiology) Genes, Tumor Suppressor Genomic Instability Humans Lung Neoplasms (genetics, metabolism) Mice Mice, Knockout Spindle Apparatus (metabolism) Tumor Suppressor Proteins (genetics, metabolism, physiology) Ubiquitin Thiolesterase

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