Overexpression of the E2 ubiquitin-conjugating enzyme UbcH10 causes chromosome missegregation and tumor formation.
The anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase functions with the E2 ubiquitin-conjugating enzyme UbcH10 in the orderly progression through mitosis by marking key mitotic regulators for destruction by the 26-S proteasome. UbcH10 is overexpressed in many human cancer types and is associated with tumor progression. However, whether UbcH10 overexpression causes tumor formation is unknown. To address this central question and to define the molecular and cellular consequences of UbcH10 overexpression, we generated a series of transgenic mice in which UbcH10 was overexpressed in graded fashion. In this study, we show that UbcH10 overexpression leads to precocious degradation of cyclin B by the APC/C, supernumerary centrioles, lagging chromosomes, and aneuploidy. Importantly, we find that UbcH10 transgenic mice are prone to carcinogen-induced lung tumors and a broad spectrum of spontaneous tumors. Our results identify UbcH10 as a prominent protooncogene that causes whole chromosome instability and tumor formation over a wide gradient of overexpression levels.
van Ree
Janine H
JH
Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Jeganathan
Karthik B
KB
Malureanu
Liviu
L
van Deursen
Jan M
JM
D000782:Aneuploidy; D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D020090:Chromosome Segregation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism*
C105156:UBE2C protein, human; C546779:Ube2c protein, mouse; D044763:Ubiquitin-Conjugating Enzymes