Effect of simian virus large T antigen expression on cell cycle control and apoptosis in rat pleural mesothelial cells exposed to DNA damaging agents

Our plain-English summary of Effect of simian virus large T antigen expression on cell cycle control and apoptosis in rat pleural mesothelial cells exposed to DNA damaging agents, by V. Levresse, S. Moritz, A. Renier, et al (Oncogene, 1998).

The study

• Authors: V. Levresse, S. Moritz, A. Renier, L. Kheuang, F. Galateau-Salle, J.P. Mège, P. Piedbois, B. Salmons, W. Guenzburg, M.C. Jaurand
• Journal: Oncogene
• Published: 1998;16(8):1041-53
• Cited by: 25 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Cell cycle progression and apoptosis are controlled by regulatory proteins, including p53, of which functional alterations are linked to carcinogenesis. Recently, malignant mesothelioma (MM), a primary tumour related to asbestos exposure, alternatively to post therapeutic radiations, has proven to be an important problem in oncogenesis. The p53 protein does not seem mutated or deleted in MM but a possible inactivation by binding to other proteins [mdm2; SV40 large T antigen (Tag)] has been suggested. The present work investigated cell cycle regulation in normal rat pleural mesothelial cells (RPMC) and in RPMC expressing Tag (RPMC-TSV40), under exposure to asbestos and radiations. In RPMC, these agents induced activation of cell cycle checkpoints located at G1/S and G2/M and/or mitosis but a lack of control at G1/S was found in RPMC-TSV40. A loss of G2/M control may account for the formation of micronuclei observed after exposure of RPMC-TSV40 to radiations. In RPMC-TSV40 the enhancement of abnormal mitoses and apoptosis after asbestos exposure, in comparison with RPMC, suggests a loss of mitotic control and a p53-independent mechanism of apoptosis. Thus Tag expression in mesothelial cells might have both adverse and beneficial effects by impairing the control of DNA integrity and enhancing apoptosis respectively.

In plain English

This was a laboratory study of rat pleural mesothelial cells grown in culture, not a study of people. The authors compared normal cells with cells engineered to carry the SV40 large T antigen, a viral protein that binds p53, a protein involved in controlling cell division. Both cell types were exposed to UICC Rhodesian chrysotile, crocidolite, or gamma radiation. Normal cells slowed their division after these exposures. The large T cells did not stop at the early (G1/S) checkpoint. After 24 Gy of radiation, 41.3% of large T cells showed nuclear abnormalities, mostly micronuclei, against 3.8% of normal cells. After 48 hours of asbestos, 20% (chrysotile) and 34% (crocidolite) of large T cell metaphases kept a near-normal chromosome number, against 78% and 64% of normal cells. Apoptosis (programmed cell death) after 48 hours of chrysotile reached 16.4% in large T cells, against 3% in normal cells at the highest concentrations. The authors concluded that large T antigen weakened control of DNA integrity but increased apoptosis. They cautioned that other investigators had not found SV40 in human mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: laboratory (in vitro) experiment comparing normal rat pleural mesothelial cells with the same cells engineered to express SV40 large T antigen
• Who was studied: cultured rat pleural mesothelial cells (RPMC) from the parietal pleura, and RPMC infected with a retroviral vector encoding SV40 large T antigen (RPMC-TSV40)
• Exposure: UICC Rhodesian chrysotile and crocidolite fibres, at a concentration printed as 10 mg/cm2, for 4, 24, 48 and 72 h. Comparison exposures were gamma radiation at 16 and 24 Gy (cobalt source) and the mitotic inhibitor nocodazole.
• Main results:
  • After gamma irradiation, normal RPMC showed increased p53, strong p21 induction and fewer replicating cells. RPMC-TSV40 showed no blockade of proliferation.
  • In normal RPMC, the number of cells in the G2/M phase rose after both chrysotile and crocidolite exposure.
  • In RPMC-TSV40 exposed to chrysotile, p53 expression did not change and p21 was not expressed.
  • After 24 Gy of radiation, nuclear aberrations were found in 3.8% of normal RPMC and 41.3% of RPMC-TSV40. In RPMC-TSV40, 36.1% of total cells had micronuclei.
  • After chrysotile exposure, binucleated cells were 14.4% in RPMC versus 26.5% in RPMC-TSV40. Multinucleated cells were 0.8% versus 2.9%.
  • After 48 h of asbestos, near-diploid metaphases in normal RPMC were 78% (chrysotile) and 64% (crocidolite). In RPMC-TSV40 they were 20% and 34%. Untreated cells were 80% (RPMC) and 48% (RPMC-TSV40). Fifty metaphases were analysed per treatment.
  • In normal RPMC, apoptotic cells reached 1.5% after radiation and 3% after chrysotile at the highest concentrations tested. The authors state crocidolite had no significant effect in these cells.
  • In RPMC-TSV40, apoptotic cells were 16.4% after 48 h of chrysotile and 8.3% after 48 h of crocidolite. Radiation produced only a slight increase.
• The authors' conclusion: The authors concluded that, in their cell system, large T antigen did not protect cells against apoptosis but enhanced it. They also concluded that large T antigen emphasized genomic instability. They suggested that large T expression may have both an adverse effect (impaired control of DNA integrity) and a beneficial effect (enhanced apoptosis).
• Limitations the authors state:
  • The authors note that the model may appear unrealistic because SV40 is not known to infect human cells.
  • The authors caution against extrapolation because other investigators failed to detect SV40 sequences in mesothelioma.
  • The authors state that differences between the two cell types may involve pRb inactivation, not only p53.

Topics

Medical terms in this study, explained in our Lexicon: Apoptosis, Mesothelial Cells, Carcinogenesis, Malignant Mesothelioma, Asbestos Exposure, Oncogenesis, SV40, Micronuclei.

Related studies

• Analysis of cell cycle disruptions in cultures of rat pleural mesothelial cells exposed to asbestos fibers — V. Levresse, A. Renier, et al. (1997)
• Simian virus-40 large-T antigen binds p53 in human mesotheliomas — M. Carbone, P. Rizzo, et al. (1997)
• Patterns of c-fos and c-jun proto-oncogene expression, apoptosis, and proliferation in rat pleural mesothelial cells exposed to erionite or asbestos fibers — C.R. Timblin, G.D. Guthrie, et al. (1998)
• The retinoblastoma gene family pRb/p105, p107, pRb2/p130 and simian virus-40 large T-antigen in human mesotheliomas — A. De Luca, A. Baldi, et al. (1997)
• SV40 oncoproteins enhance asbestos-induced DNA double-strand breaks and abrogate senescence in murine mesothelial cells — J.R. Pietruska, A.B. Kane (2007)
• The presence of simian-virus 40 sequences in mesothelioma and mesothelial cells is associated with high levels of vascular endothelial growth factor — P. Cacciotti, L. Strizzi, et al. (2002)

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