Schwab, RAV;
(2007)
Investigating the role of the transcription factor b-Myb in neuroblastoma.
Doctoral thesis , UCL (University College London).
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Abstract
The transcription factor B-MYB is involved in the regulation of proliferation, differentiation and apoptosis. Several lines of evidence indicate that aberrant expression of B-MYB might contribute to cancer. A link between B-MYB and neuroblastoma, a paediatric malignancy derived from the sympathoadrenal cell lineage, was proposed as B-MYB expression in primary neuroblastoma biopsies was significantly correlated with reduced patient survival. While attempting downregulation of B-MYB by RNAi techniques for therapeutic purposes, we found that the B-MYB protein is highly stable in neuroblastoma cell lines and increased B-MYB stability correlates with enhanced cell survival after UV-treatment. Increased B-MYB stability may be functionally relevant as cell survival is augmented upon ectopic B-MYB expression and decreased in the presence of dominant negative B-MYB. By comparing the B-MYB phosphorylation levels in a number of cancer cell lines, we detected that B-MYB phosphorylation is low in neuroblastoma cells and inhibition of B-MYB phosphorylation renders the protein more stable. We show that the phosphorylation deficient B-MYB mutant is functionally active in promoting cell survival after UV-irradiation and thus non- degradable B-MYB could promote survival of cells bearing genomic lesions that would normally be eliminated by cell death. Whereas no gross sequence abnormalities were identified, sequencing of the coding region of B-MYB from various neuroblastoma cell lines revealed two single nucleotide polymorphisms (SNPs). These do not contribute to enhanced B-MYB stability, but both polymorphic variants are hypomorphic and are significantly less frequent in a cohort of cancer patients, including neuroblastoma patients. This suggests that individuals with these B-MYB variants may have a lower incidence of cancer. Our results indicate that under certain circumstances, high doses of wild type B-MYB, potentially resulting from abnormal protein stabilisation, can facilitate transformation by promoting cell survival, but similar levels of the polymorphic variants may not be as detrimental.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | Investigating the role of the transcription factor b-Myb in neuroblastoma |
| Identifier: | PQ ETD:593418 |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by ProQuest. Third party copyright material has been removed from the ethesis. Images identifying individuals have been redacted or partially redacted to protect their identity. |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1446089 |
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