Abstract
SV40 large T antigen (T) inactivates the tumor suppressor proteins p53 and pRb, and can induce cells to enter DNA replication at inappropriate times. We show here that T also compromises three cell cycle checkpoints that regulate the entry into and exit from mitosis. Human diploid fibroblasts infected with a retrovirus expressing T displayed an attenuated radiation-induced mitotic delay, were more susceptible to chemical-induced uncoupling of mitosis from the completion of DNA replication, and were more likely to exit mitosis and rereplicate their DNA when mitotic spindle assembly was inhibited. Consistent with altered mitotic checkpoint control, cells expressing T displayed elevated protein levels and/or associated activities of the mitotic regulatory proteins cyclin A, cyclin B, Cdc25C and p34cdc2. These changes in mitotic control were evident within 5 – 10 population doublings after retroviral infection, indicating a direct effect of T expression. Cells acutely infected with the T-expressing retrovirus suffered numerical and structural chromosome aberrations, including increases in aneuploidy, dicentric chromosomes, chromatid exchanges and chromosome breaks and gaps. These findings indicate that T rapidly disrupts mitotic checkpoints that help maintain genomic stability, and suggest mechanisms by which T induces chromosome aberrations and promotes the immortalization and neoplastic transformation of human cells.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Chang, TT., Ray, F., Thompson, D. et al. Disregulation of mitotic checkpoints and regulatory proteins following acute expression of SV40 large T antigen in diploid human cells. Oncogene 14, 2383–2393 (1997). https://doi.org/10.1038/sj.onc.1201196
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1201196
Keywords
This article is cited by
-
Conditional immortalization of human atrial myocytes for the generation of in vitro models of atrial fibrillation
Nature Biomedical Engineering (2022)
-
Immortalization of primary sheep embryo kidney cells
In Vitro Cellular & Developmental Biology - Animal (2021)
-
Chronic iron exposure and c-Myc/H-ras-mediated transformation in fallopian tube cells alter the expression of EVI1, amplified at 3q26.2 in ovarian cancer
Oncogenesis (2019)
-
Occurrence of TRGV-BJ hybrid gene in SV40-transformed fibroblast cell lines
Genetica (2009)
-
Construction of an immortalized neural progenitor cell strain and analysis of its immunogenicity
Frontiers of Medicine in China (2008)