title: Aneuploidy and telomere attrition are independent determinants of crisis in SV40-transformed epithelial cells.
abstract: Replicative immortality is achieved in vitro by overcoming two mortality checkpoints, M1 (senescence) and M2 (crisis). Cancer cells are thought to overcome M2 by activating telomerase, an enzyme believed to confer genomic stability in addition to maintaining telomeric sequences above a critical length. Here we show that a subset of cultured ovarian cystadenoma cells expressing SV40 large T-antigen, which allows bypassing of M1, develop a specific type of genomic instability, characterized by numerical (as opposed to structural) chromosomal alterations, that leads to non-telomere-based premature growth arrest/crisis. Cells recover from this type of growth arrest and stabilize their ploidy status without telomerase expression. In these cases, telomeres continue to shorten until a second, telomere-based growth arrest/crisis event is reached. Transfection of the catalytic subunit of telomerase does not immortalize cells harboring severe abnormalities in their DNA ploidy but results in immortalization of diploid cells. We conclude that changes in DNA ploidy constitute an important determinant of growth arrest that is independent of telomere attrition in a subset of SV40 large T-antigen-expressing cystadenoma cells. Reestablishment or emergence of ploidy stability, which is not always dependent on telomerase activation, is necessary for acquisition of the potential to achieve replicative immortality.
authors.affiliation: University of Southern California/Norris Comprehensive Cancer Center, Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles, California 90089-9181, USA.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Velicescu
authors.forename: Jiamei
authors.initials: J
authors.lastname: Yu
authors.forename: Brittney-Shea
authors.initials: BS
authors.lastname: Herbert
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
authors.forename: Eileen
authors.initials: E
authors.lastname: Granada
authors.forename: Louis
authors.initials: L
authors.lastname: Dubeau
mesh_terms: D000782:Aneuploidy; D000952:Antigens, Polyomavirus Transforming / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral / Q000235:genetics*; D003537:Cystadenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins; D004171:Diploidy; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000473:pathology / Q000502:physiology; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013539:Simian virus 40; D019098:Telomerase / Q000096:biosynthesis / Q000378:metabolism; D016615:Telomere / Q000235:genetics*
chemical_list: D000952:Antigens, Polyomavirus Transforming; D004268:DNA-Binding Proteins; D019098:Telomerase