The role of p53.S389 phosphorylation in DNA damage response pathways and tumorigenesis

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The role of p53.S389 phosphorylation in DNA damage response pathways and tumorigenesis

Type: Doctoral Thesis
Title: The role of p53.S389 phosphorylation in DNA damage response pathways and tumorigenesis
Author: Bruins, W.
Publisher: Department Toxicogenetics, Medicine / Leiden University Medical Center (LUMC), Leiden University
Issue Date: 2007-10-24
Keywords: Carcinogenesis
DNA repair
Microarray
Mutant mouse model
p53
Phosphorylation
UV
Abstract: 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 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.
Promotor: Supervisor: Steeg H. van Co-Supervisor: Vries A. de
Faculty: Leiden University Medical Center (LUMC)
University: Leiden University
Handle: http://hdl.handle.net/1887/12389
 

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