University of Oulu

Mechanism of benzo(a)pyrene-induced accumulation of p53 tumour suppressor protein in mouse

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Author: Serpi, Raisa1
Organizations: 1University of Oulu, Faculty of Medicine, Department of Pharmacology and Toxicology
Format: ebook
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.8 MB)
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Language: English
Published: 2003
Publish Date: 2003-06-13
Thesis type: Doctoral Dissertation
Defence Note: Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in the Auditorium of the Department of Pharmacology and Toxicology, on June 13th, 2003, at 12 noon.
Reviewer: Docent Hannu Komulainen
Professor Veli-Matti Kosma


The tumour suppressor gene TP53 is the most commonly mutated gene in human cancers. The protein it codes, p53, becomes activated as a response to stress signals. When activated, p53 binds to DNA and affects the transcription of its target genes. They then cause cell cycle arrest, DNA repair and/or induction of programmed cell death, thus preventing mutations and cancer. Specific mutations in TP53 are associated with exposure to certain carcinogens, such as polycyclic aromatic hydrocarbons (PAHs). These environmental chemical carcinogens are formed through incomplete combustion of organic material. Benzo(a)pyrene (BP) is commonly used as a model compound for PAH carcinogenesis. BP causes accumulation of p53, but the mechanism of accumulation is not known. The aim of this study was to gain more insight into the p53 protein in the first phases of PAH carcinogenesis in vivo in mouse, using BP as the model compound.

Mice from the inbred C57BL/6 strain were treated topically or intraperitoneally with BP or were exposed to cigarette smoke inhalation. The amount of p53 protein was studied by immunoblotting, immunohistochemistry and immuno electron microscopy, and the mdm2, p21 and p19ARF proteins were studied by immunoblotting. The binding of BP to DNA was measured by synchronous fluorescence spectrophotometry.

The p53 protein was induced in vivo in skin and lung after BP treatment and in lung after cigarette smoke treatment. An increase in p53 was associated with an increase in the amount of BP-DNA adducts. In skin, the induction of p53 was accompanied by induction of the p21 and mdm2 proteins, which are transcriptional targets of p53. This indicates that the in vivo induced p53 is a wild-type protein and functional. In lungs, the induction of p53 was accompanied by a decrease of mdm2 and an increase of p19ARF. These results confirm that BP is metabolized and binds to DNA in mouse tissues and indicate that BP-DNA adducts are the trigger for p53 protein induction. The in vivo regulation of the p53 protein is different in different tissues of C57BL/6 mouse.

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Series: Acta Universitatis Ouluensis. D, Medica
ISSN-E: 1796-2234
ISBN: 951-42-7039-8
ISBN Print: 951-42-7038-X
Issue: 731
Copyright information: © University of Oulu, 2003. This publication is copyrighted. You may download, display and print it for your own personal use. Commercial use is prohibited.