Robson, Samuel Charles (2008) Life or cell death: identifying c-Myc regulated genes in two distinct tissues. PhD thesis, University of Warwick.

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Abstract

The c-myc oncogene is over-expressed or deregulated in many human cancers. c-myc encodes a transcription factor, the oncoprotein c-Myc (Myc), which acts as a master regulator of genes involved in such diverse cellular processes as replication and growth, loss of differentiation, invasion, and angiogenesis. Myc can also act as its own tumour suppressor by promoting cell death in the form of apoptosis. Thus, for putative cancer cells to arise, apoptosis must be blocked. Conditional MycERTAM transgenic mice allow regulated activation of Myc in distinct cell populations (skin suprabasal keratinocytes and pancreatic islet β-cells) and have highlighted contrasting behaviour between these two adult tissues in vivo: proliferation in the skin, and apoptosis in the pancreas. Given the crucial dependence on tissue location in vivo, we still do not know enough about the key divergence in Myc-regulated genes and proteins under conditions favouring opposing outcomes. To address this, we performed high-throughput transcriptome analysis using oligonucleotide microarrays. The in vivo transcriptional response to deregulated Myc was analysed for skin keratinocytes and laser-captured pancreatic islets following a time-course of MycERTAM activation. Due to the multi-factorial nature of the experimental design, novel statistical tools were developed allowing the use of linear models for inference of changes in gene-expression based on multiple experimental variables. Comparison of the transcriptional response between the two tissues identified potential signalling pathways which may promote apoptosis of β-cells or survival of skin keratinocytes: the DNA damage response pathway, and the Insulin-like growth factor 1 (Igf1) signalling pathway respectively. In addition, a marked change in expression was detected in members of the steroid hormone-regulated Kallikrein serine protease family in suprabasal keratinocytes but not for β-cells. These have been found to play an important role in regulating Igf1/Igf1-receptor ligation through proteolysis of the Igf1 binding proteins, are previously categorised markers for several human cancers, and may indicate a tissue-specific regulatory mechanism for determining ultimate Myc function in vivo.

Item Type:	Thesis or Dissertation (PhD)
Subjects:	Q Science > QH Natural history > QH426 Genetics
Library of Congress Subject Headings (LCSH):	Oncogenes -- Research, Myc proteins -- Research, Transcription factors, Cell death -- Research, Apoptosis, Keratinocytes
Official Date:	21 November 2008
Dates:	Date Event 21 November 2008 Submitted
Institution:	University of Warwick
Theses Department:	Department of Chemistry
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Khan, Michael ; Epstein, D. B. A. ; Pelengaris, Stella
Sponsors:	Engineering and Physical Sciences Research Council (Great Britain) (EPSRC) ; Molecular Organisation and Assembly in Cells (MOAC) Doctoral Training Centre ; Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC) ; Association for International Cancer Research (AICR) ; Eli Lilly and Company (EL&C) ; Amylin Pharmaceuticals (AP)
Format of File:	pdf
Extent:	482 leaves : col. ill., charts
Language:	eng

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