Sunlight has many beneficial effects. However, from a biological point of view, solar UV radiation has also detrimental effects, especially at high doses of exposure. Because of its genotoxic... Show moreSunlight has many beneficial effects. However, from a biological point of view, solar UV radiation has also detrimental effects, especially at high doses of exposure. Because of its genotoxic properties, UV radiation plays an important role in the induction of skin cancer. In the last decennia, the incidence of skin cancer is rapidly increasing. This can partly be explained by an ageing population. However, the rise in skin cancer incidence appears to be primarily due to a change in human lifestyle in which sunbathing has become very popular. Our skin is continuously challenged by UV radiation, which may lead to irreversible damage. In order to withstand sustained physical, chemical and biological damage from the environment, among which UV radiation, the skin is continuously renewed. The regenerative capacity of skin is conferred by stem cells, which persist throughout the organism__s lifetime. Because of their long residency and unlimited capacity to replicate, stem cells might accumulate DNA damage and generate the multiple genetic lesions necessary for tumour development, despite efficient cellular defence mechanisms against DNA damage. Thus, stem cells may play an important role in carcinogenesis. The aim of this study is to investigate the role of stem cells in skin carcinogenesis. Show less
The results presented in this thesis provide new information on the role of the p53.S389A point mutation in chemical-induced tumorigenesis. After DNA damage, p53 protein levels increase due to... Show moreThe results presented in this thesis provide new information on the role of the p53.S389A point mutation in chemical-induced tumorigenesis. After DNA damage, p53 protein levels increase due to several post-translational activation processes. Phosphorylation of p53.S389 seems to be partly required for optimal induction of these p53 protein levels. Next, target genes are either induced or repressed, and phosphorylation of p53.S389 seems essential for an optimal p53-related transcriptional response both endogenously (especially repressed genes) as well as after the induction of DNA damage. Than as a read-out system for the activation of different genes, several cellular responses (apoptosis, cell cycle arrest etc.) can be observed, which again seems partly dependent on p53.S389 phosphorylation. When these processes are adversely affected due to inadequate functioning of p53, like is the case in p53.S389A mutant mice, this might lead to increased risks of developing tumors. Indeed, two chronic carcinogenicity experiments revealed an increased sensitivity of the p53.S389A mutant mice for tumor development upon exposure to DNA damaging agents. In conclusion, knowledge about the in vivo relationship between DNA damage induction, regulation of p53 activity (in terms of cell cycle control and/or apoptosis), DNA repair (NER) and the development of cancer was obtained. Show less
