title: 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.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Oded
authors.initials: O
authors.lastname: Foreman
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Wigle
authors.forename: Farhad
authors.initials: F
authors.lastname: Kosari
authors.forename: George
authors.initials: G
authors.lastname: Vasmatzis
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Salisbury
authors.forename: Jan
authors.initials: J
authors.lastname: van Deursen
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Galardy
mesh_terms: D059786:Abnormal Karyotype; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D000077192:Adenocarcinoma of Lung; D000782:Aneuploidy; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D018385:Centrosome / Q000378:metabolism*; D020090:Chromosome Segregation; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016147:Genes, Tumor Suppressor; D042822:Genomic Instability; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008941:Spindle Apparatus / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D043222:Ubiquitin Thiolesterase
chemical_list: D002135:Calcium-Binding Proteins; C424436:Cetn2 protein, mouse; D025521:Tumor Suppressor Proteins; D010450:Endopeptidases; C577772:USP44 protein, mouse; D043222:Ubiquitin Thiolesterase