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

Author(s):
Bruins, W.
Published
2007
Publication type
Doctoral Thesis

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.

CarcinogenesisDNA repairMicroarrayMutant mouse modelp53PhosphorylationUV
Defense date
2007-10-24
Language
English
Supervisor(s)
Steeg, H. van
Advisor(s)
Vries, A. de
Qualification
Ph.D.
Degree granting institution
Leiden University Medical Center (LUMC), Leiden University, Leiden
Publisher
Department Toxicogenetics, Medicine / Leiden University Medical Center (LUMC), Leiden University
hdl
1887/12389

Funding

Sponsorship
The research described in this thesis was financially supported by a grant (RIVM 2000-2352) of the Dutch Cancer Society (KWF), by a grant (1UO1 ES11044) of the National Institutes of Health/National Institute of Environmental Health Sciences (NIH/NIEHS) concerning the Comparative Mouse Genomics Centers Consortium (CMGCC) and by a BSIK grant through the Netherlands Genomics Initiative (NGI) in the context of the BioRange program of the Netherlands Bioinformatics Centre (NBIC). The printing of this thesis was financially supported by Stichting Nationaal Fonds tegen Kanker te Amsterdam, Nutricia Nederland B.V., Greiner Bio-One, BD biosciences, the National Institute of Public Health and the Environment (RIVM) and the Leiden University Medical Center (LUMC).