Das Tumorsuppressorprotein p53 - Rolle bei der Induktion von Apoptose und bei der Replikation von Adenoviren
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Philipps-Universität Marburg
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Abstract
The tumor suppressor p53 is a central regulator
of proliferation and cell growth. It has become the subject of
intensive study ever since it became clear that slightly more
than 50% of human cancers contain mutations in this gene.
Several types of DNA-damage can activate wildtype-p53. The
result is a rapid increase in the level of p53 and activation
of p53 as a transcriptional factor. p53 induces two major
pathways, cell cycle arrest and/or apoptosis. p53 is also a
target of viral oncoproteins. The adenoviral oncoproteins
E1B-55kD and E4orf6 inactivate and destabilize p53, thereby
contributing to malignant transformation. However, it is
unclear whether the elimination of p53 contributes to the
efficiency of viral replication. Furthermore, it is
controversial whether adenoviruses with a deletion in the
E1B55kD-coding region (dl1520/ ONYX 015) might selectively
replicate in cells with a mutation or deletion of the p53 gene
and, therefore, represent a tool in cancer therapy.
A p53
protein lacking the proline-rich region (p53delta62-91) induces
many p53-responsive genes but not PIG3. In parallel, this
mutant induces growth arrest but not apoptosis. Some
tumor-derived p53-mutants, especially p53M264I, specifically
failed to induce the PIG3 promoter and apoptosis, thus
resembling p53delta62-91. These results suggest that the
proline-rich domain of p53 affects the ability of the central
domain to bind DNA.
Furthermore, an assay was established to
identify other p53-responsive genes showing the same activation
pattern as PIG3. Therefore, p53 (-/-) H1299 cells were
tranduced by adenoviral vectors to express p53 or
p53delta62-91. Differentially activated p53-responsive genes
were compared by cDNA-arrays. A p53-responsive gene was
identified (Ephrin-B4-Receptor) that showed the same pattern of
activation as PIG3. Therefore, this gene represents a candidate
mediator of p53 induced apoptosis.
To address the role of p53
in virus replication, a p53-mutant has been constructed
(p53mt24-28). This mutation leaves p53 transcriptionally active
but confers complete resistance to inhibition and degradation
by adenoviral oncoproteins. This mutant was expressed by an
adenoviral vector. Surprisingly, even strong overexpression of
p53 or p53mt24-28 allowed the virus to replicate as efficiently
as in the absence of p53 proteins, both in tumor cells and in
primary cells. Thus, active p53 does not inhibit the growth of
adenovirus. Instead of deleting the p53-antagonist E1B-55kD,
alternative strategies should be used to improve the utility of
adenoviruses in cancer therapy.The tumor suppressor p53 is a central regulator
of proliferation and cell growth. It has become the subject of
intensive study ever since it became clear that slightly more
than 50% of human cancers contain mutations in this gene.
Several types of DNA-damage can activate wildtype-p53. The
result is a rapid increase in the level of p53 and activation
of p53 as a transcriptional factor. p53 induces two major
pathways, cell cycle arrest and/or apoptosis. p53 is also a
target of viral oncoproteins. The adenoviral oncoproteins
E1B-55kD and E4orf6 inactivate and destabilize p53, thereby
contributing to malignant transformation. However, it is
unclear whether the elimination of p53 contributes to the
efficiency of viral replication. Furthermore, it is
controversial whether adenoviruses with a deletion in the
E1B55kD-coding region (dl1520/ ONYX 015) might selectively
replicate in cells with a mutation or deletion of the p53 gene
and, therefore, represent a tool in cancer therapy.
A p53
protein lacking the proline-rich region (p53delta62-91) induces
many p53-responsive genes but not PIG3. In parallel, this
mutant induces growth arrest but not apoptosis. Some
tumor-derived p53-mutants, especially p53M264I, specifically
failed to induce the PIG3 promoter and apoptosis, thus
resembling p53delta62-91. These results suggest that the
proline-rich domain of p53 affects the ability of the central
domain to bind DNA.
Furthermore, an assay was established to
identify other p53-responsive genes showing the same activation
pattern as PIG3. Therefore, p53 (-/-) H1299 cells were
tranduced by adenoviral vectors to express p53 or
p53delta62-91. Differentially activated p53-responsive genes
were compared by cDNA-arrays. A p53-responsive gene was
identified (Ephrin-B4-Receptor) that showed the same pattern of
activation as PIG3. Therefore, this gene represents a candidate
mediator of p53 induced apoptosis.
To address the role of p53
in virus replication, a p53-mutant has been constructed
(p53mt24-28). This mutation leaves p53 transcriptionally active
but confers complete resistance to inhibition and degradation
by adenoviral oncoproteins. This mutant was expressed by an
adenoviral vector. Surprisingly, even strong overexpression of
p53 or p53mt24-28 allowed the virus to replicate as efficiently
as in the absence of p53 proteins, both in tumor cells and in
primary cells. Thus, active p53 does not inhibit the growth of
adenovirus. Instead of deleting the p53-antagonist E1B-55kD,
alternative strategies should be used to improve the utility of
adenoviruses in cancer therapy.
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Metadata
Dates
Created: 2003Issued: 2003-12-22Updated: 2011-08-10
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
apoptosis , adenovirusTumorsuppressorgen , Tumorsuppressorproteinp53p53
DFG-subjects
ApoptosisAdenoviren , DNS-Tumorviren
DDC-Numbers
610
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Koch, Philipp (104872942): Das Tumorsuppressorprotein p53 - Rolle bei der Induktion von Apoptose und bei der Replikation von Adenoviren. : Philipps-Universität Marburg 2003-12-22. DOI: https://doi.org/10.17192/z2003.0699.
License
This item has been published with the following license: In Copyright