High levels of MDM2 are not correlated with the presence of wild-type p53 in human malignant mesothelioma cell lines

Our plain-English summary of High levels of MDM2 are not correlated with the presence of wild-type p53 in human malignant mesothelioma cell lines, by S. Ungar, A. Van de Meeren, L. Tammilehto, et al (British Journal of Cancer, 1996).

The study

• Authors: S. Ungar, A. Van de Meeren, L. Tammilehto, K. Linnainmaa, K. Mattson, B.I. Gerwin
• Journal: British Journal of Cancer
• Published: 1996;74(10):1534-40
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Prior analysis of 20 human mesothelioma cell lines for p53 status revealed only two mutations and one p53 null cell line, although p53 expression was detected in most cell lines. In addition, mRNA and protein expression of the retinoblastoma gene product in human mesothelioma cell lines is similar to normal controls. We have tested for p53 induction after exposure to ionising radiation and demonstrate this induction and, to a lesser extent, p21(WAF1) induction, in both normal mesothelial cells and p53-positive mesothelioma cell lines. We postulated that high levels of MDM2 might alter p53 and retinoblastoma tumour-suppressor function in mesothelioma. However, Southern blot analysis for mdm2 indicated that no amplification had occurred in 18 mesothelioma cell lines tested. Steady-state mRNA and protein levels also did not indicate overexpression. These results indicate that high levels of MDM2 are not responsible for inactivating the functions of wild-type p53 or the retinoblastoma gene product during the pathogenesis of malignant mesothelioma.

In plain English

This laboratory study used human malignant mesothelioma cell lines grown in culture. It did not study asbestos exposure. The authors proposed that high levels of MDM2, a protein that can block the tumour-suppressor proteins p53 and Rb, might disable these pathways in mesothelioma even though most lines carry normal (wild-type) p53. After 3.5 Gy of ionising radiation, p53 and p21WAF1 were induced in five of six mesothelioma lines tested. In 18 mesothelioma lines, the mdm2 gene was not amplified: gene content was 1.0 to 1.7 relative to bronchial fibroblast cells. MDM2 mRNA in the cancer lines ranged from 1.0 to 5.1 relative to the VAMT-1 line. In four normal mesothelial cultures, three ranged from 1.4 to 3.6 relative to VAMT-1, and one showed a 10.5-fold excess. MDM2 protein, measured relative to bronchial fibroblast cells, ranged from 0.1 to 5.8 in the cancer lines and from 1.2 to 9.8 in five normal mesothelial samples. MDM2 levels did not consistently track p53 status. The authors concluded that high MDM2 is not a major factor in malignant mesothelioma. They noted that there were few normal samples and that the expression measures were in arbitrary units.

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) study of cultured human cell lines, using radiation experiments plus DNA, mRNA and protein analyses
• Who was studied: 18 human malignant mesothelioma cell lines previously characterised for p53. They were compared with primary cultures of normal human mesothelial (NHM) cells (four for mRNA, five for protein), human bronchial fibroblastic (HBF) cells, normal human bronchial epithelial cells, and an MDM2-overexpressing sarcoma line (OSA-Cl). This text does not say where or when the lines were derived.
• Exposure: No asbestos or fibre exposure was studied. As an experimental test of p53 function, cells were exposed to 3.5 Gy of ionising radiation for 1 minute.
• Main results:
  • Ionising radiation induced nuclear accumulation of p53 and p21WAF1 in five of six mesothelioma lines tested that express wild-type p53.
  • The M28K mesothelioma line showed no nuclear p53 in either control or irradiated cells.
  • The mdm2 gene was not amplified in the 18 mesothelioma lines. Gene content relative to HBF cells ranged from 1.0 to 1.7.
  • MDM2 mRNA in the mesothelioma lines ranged from 1.0 to 5.1 relative to VAMT-1, a variation similar to that seen in the normal mesothelial cells.
  • In the four normal mesothelial cultures, three had MDM2 mRNA of 1.4 to 3.6 relative to VAMT-1, and one showed 10.5-fold elevated expression.
  • MDM2 protein relative to HBF ranged from 0.1 to 5.8 in the 18 mesothelioma lines and from 1.2 to 9.8 in five normal mesothelial samples.
  • The p53-null VAMT-1 line showed a 10-fold reduction in MDM2 protein compared with HBF.
  • Lines with elevated wild-type p53 (M9K, M32K, DND) did not show consistently elevated mdm2 mRNA. MDM2 levels therefore did not correlate with wild-type p53.
• The authors' conclusion: The authors concluded that disruption of the wild-type p53 and Rb tumour-suppressor pathways by high levels of MDM2 protein is not a major factor in the aetiology of malignant mesothelioma. They suggested that other, uncharacterised downstream factors in these pathways could be altered.
• Limitations the authors state:
  • Only a few normal mesothelial samples were available (four for mRNA), which does not allow broad conclusions about the normal range of expression.
  • All expression ratios are arbitrary numbers and were not normalised to an absolute concentration standard.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Mesothelial Cells.

Related studies

• Adenovirus-mediated wild-type p53 overexpression reverts tumourigenicity of human mesothelioma cells — M. Giuliano, A. Catalano, et al. (2000)
• Combination of a p53-activating CP-31398 and an MDM2 or a FAK inhibitor produces growth suppressive effects in mesothelioma with wild-type p53 genotype — B. Zhong, M. Shingyoji, et al. (2020)
• Upregulated p53 expression activates apoptotic pathways in wild-type p53-bearing mesothelioma and enhances cytotoxicity of cisplatin and pemetrexed — Q. Li, K. Kawamura, et al. (2012)
• Whole exome sequencing of an asbestos-induced wild-type murine model of malignant mesothelioma — S. Sneddon, A.M. Patch, et al. (2017)
• Gender comparisons in human lung cancer: analysis of p53 mutations, anti-p53 serum antibodies and C-erbB-2 expression — D.G. Guinee, W.D. Travis, et al. (1995)
• Simian virus-40 large-T antigen binds p53 in human mesotheliomas — M. Carbone, P. Rizzo, et al. (1997)

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