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Hypoxia induces p53-dependent transactivation and Fas/CD95-dependent apoptosis
KTH, School of Biotechnology (BIO), Gene Technology.
KTH, School of Biotechnology (BIO), Gene Technology.
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2007 (English)In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 14, no 3, 411-421 p.Article in journal (Refereed) Published
Abstract [en]

p53 triggers apoptosis in response to cellular stress. We analyzed p53-dependent gene and protein expression in response to hypoxia using wild-type p53-carrying or p53 null HCT116 colon carcinoma cells. Hypoxia induced p53 protein levels and p53-dependent apoptosis in these cells. cDNA microarray analysis revealed that only a limited number of genes were regulated by p53 upon hypoxia. Most classical p53 target genes were not upregulated. However, we found that Fas/CD95 was significantly induced in response to hypoxia in a p53-dependent manner, along with several novel p53 target genes including ANXA1, DDIT3/ GADD153 (CHOP), SEL1L and SMURF1. Disruption of Fas/CD95 signalling using anti-Fas-blocking antibody or a caspase 8 inhibitor abrogated p53-induced apoptosis in response to hypoxia. We conclude that hypoxia triggers a p53-dependent gene expression pattern distinct from that induced by other stress agents and that Fas/CD95 is a critical regulator of p53-dependent apoptosis upon hypoxia.

Place, publisher, year, edition, pages
2007. Vol. 14, no 3, 411-421 p.
Keyword [en]
p53, hypoxia, apoptosis, microarray analysis, p53 target genes
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:kth:diva-6653DOI: 10.1038/sj.cdd.4402022ISI: 000244275400004ScopusID: 2-s2.0-33847077136OAI: diva2:11423

QC 20100907

Available from: 2006-12-15 Created: 2006-12-15 Last updated: 2014-11-17Bibliographically approved
In thesis
1. Microarray Based Gene Expression Analysis in Cancer Research
Open this publication in new window or tab >>Microarray Based Gene Expression Analysis in Cancer Research
2006 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

Biotechnological inventions during the 20th century have resulted in a wide range of approaches for explorations in the functional genomics field. Microarray technology is one of the recent advances which have provided us with snapshots of which genes are expressed in cells of various tissues and diseases. Methods to obtain reliable microarray data are continuously being developed and improved to meet the demands of biological researchers.

In this thesis microarrays have been used to investigate gene expression patterns in cancer research. Four studies in three different areas were carried out covering adrenocortical tumors, p53 target genes and a comparison of RNA amplification methods.

Adrenocortical tumours are among the most common tumours with an incidence of 7-9%. Malignancy of these tumors is rare. Distinction between malignant and benign tumours is often difficult to establish which makes an improvement of diagnostic approaches important. To elucidate biological processes in adrenocortical tumour development and to examine if there is a molecular signature associated with malignancy, microarray analysis was performed on 29 adrenocortical tumors and four normal specimens. It was possible to classify malignant and benign samples based on the entire expression profile. A number of potential biomarkers was identified which will be further evaluated.

P53 is a gene which is mutated in 50% of all cancers. Functional p53 is a transcription factor which is activated upon cellular stress and DNA damage. Target genes are mainly involved in cell cycle arrest and apoptosis. In solid tumors cells are stressed by hypoxia. To examine which target genes p53 activate under hypoxic conditions a microarray study of the cell lines HCT116p53+/+ and HCT116p53-/- was performed. A set of novel potential p53 target genes was identified while many known target genes were found to be not transcriptionally activated during hypoxia. Follow up which was focused on how p53 affected hypoxia induced apoptosis showed that the death receptor Fas was critical.

When small amounts of tissue are available, amplification of the transcript population is necessary for microarray analysis. A new strategy for amplification based on PCR was evaluated and compared to a commercial in vitro transcription protocol. Both protocols produced reliable results. Advantages with the PCR based method are a lower cost and a high flexibility due to compatibility with both sense and antisense strand microarrays.

Keywords: adrenocortical tumour, apoptosis, cancer, classification, gene expression, microarray, p53, RNA amplification

Place, publisher, year, edition, pages
Stockholm: KTH, 2006. 76 p.
adrenocortical tumour, apoptosis, cancer, classification, gene expression, microarray, p53, RNA amplification
National Category
Cell and Molecular Biology
urn:nbn:se:kth:diva-4244 (URN)91-7178-542-6 (ISBN)978-91-7178-542-8 (ISBN)
Public defence
2006-12-22, FD5, AlbaNova Universitetscentrum, Roslagstullsbacken 21, Stockholm, 10:00
QC 20100907Available from: 2006-12-15 Created: 2006-12-15 Last updated: 2010-09-07Bibliographically approved

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