Inhibition of p53 function in tumours that express the PAX3 proto-oncogene
Inhibition of p53 function in tumours that express the PAX3 proto-oncogene
Inactivating mutations in the TP53 gene are an infrequent event in tumours derived from cells of neural crest origin. The survival of cells from these tumours is often dependent upon their expression of PAX3, an embryologically expressed transcription factor that is essential for the suppression of spontaneous p53-dependent apoptosis in the developing neural crest. I hypothesized that PAX3 causes repression of p53 function in tumours of neural crest origin.
I show that PAX3 is required to prevent spontaneous p53-dependent apoptosis in melanoma cells using siRNA. Knockdown of PAX3 expression causes a loss of cell viability of over 90% and induction of the pro-apoptotic protein BAX. This is in contrast to induction of the cyclin dependent kinase inhibitor p21WAF-1 and cell cycle arrest in response to HDM2 knockdown. Furthermore, I confirm the importance of PAX3 in the survival of neuroblastoma.
In a model system PAX3 suppresses p53-dependent transcription from promoters including BAX and HDM2 but, importantly, not WAF-1. Mutagenesis studies show that this suppression is dependent upon the integrity of PAX3 as an activating transcription factor. PAX3 expression causes a reduction in p53 protein levels by up to 90% and an increase in p53 turn-over, which is not due to classical proteasomal degradation.
My data clearly demonstrates a critical role for the PAX3 oncoprotein in the inhibition of p53-dependent pro-apoptotic pathways in neural crest derived tumours. Furthermore, I have developed a cell based screening assay to identify compounds that inhibit PAX3 function in melanoma cells. Such compounds will be used as tools to study the mechanism of p53 functional inhibition by PAX3 in future work and may also have therapeutic potential.
University of Southampton
Underwood, Timothy James
4a251cf6-1568-4037-b59f-52bb9a50b9a5
2006
Underwood, Timothy James
4a251cf6-1568-4037-b59f-52bb9a50b9a5
Underwood, Timothy James
(2006)
Inhibition of p53 function in tumours that express the PAX3 proto-oncogene.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
Inactivating mutations in the TP53 gene are an infrequent event in tumours derived from cells of neural crest origin. The survival of cells from these tumours is often dependent upon their expression of PAX3, an embryologically expressed transcription factor that is essential for the suppression of spontaneous p53-dependent apoptosis in the developing neural crest. I hypothesized that PAX3 causes repression of p53 function in tumours of neural crest origin.
I show that PAX3 is required to prevent spontaneous p53-dependent apoptosis in melanoma cells using siRNA. Knockdown of PAX3 expression causes a loss of cell viability of over 90% and induction of the pro-apoptotic protein BAX. This is in contrast to induction of the cyclin dependent kinase inhibitor p21WAF-1 and cell cycle arrest in response to HDM2 knockdown. Furthermore, I confirm the importance of PAX3 in the survival of neuroblastoma.
In a model system PAX3 suppresses p53-dependent transcription from promoters including BAX and HDM2 but, importantly, not WAF-1. Mutagenesis studies show that this suppression is dependent upon the integrity of PAX3 as an activating transcription factor. PAX3 expression causes a reduction in p53 protein levels by up to 90% and an increase in p53 turn-over, which is not due to classical proteasomal degradation.
My data clearly demonstrates a critical role for the PAX3 oncoprotein in the inhibition of p53-dependent pro-apoptotic pathways in neural crest derived tumours. Furthermore, I have developed a cell based screening assay to identify compounds that inhibit PAX3 function in melanoma cells. Such compounds will be used as tools to study the mechanism of p53 functional inhibition by PAX3 in future work and may also have therapeutic potential.
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Published date: 2006
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Local EPrints ID: 466288
URI: http://eprints.soton.ac.uk/id/eprint/466288
PURE UUID: 89d4ade5-df37-4baf-850c-d95903c52b92
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Date deposited: 05 Jul 2022 05:03
Last modified: 16 Mar 2024 20:37
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Author:
Timothy James Underwood
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