Vinsamlegast notið þetta auðkenni þegar þið vitnið til verksins eða tengið í það: http://hdl.handle.net/1946/33219
Melanoma is the most lethal form of skin cancer and is most commonly caused by UV induced mutagenesis. MITF is considered the master regulator of melanocytes and has been termed a lineage survival oncogene in melanoma. As such, MITF has been extensively studied in melanoma and has been suggested to directly regulate the expression of a number of cell cycle regulatory genes. However, the link between MITF and cell cycle regulation in melanocytes has been poorly studied. This is largely due to the fact that MITF mutations, e.g. in mice, lack melanocytes. In this thesis, I developed immortalized melanocyte cell lines from mice carrying an inducible Mitf knockdown mutation called MitfK243R, with or without an inducible mutation in the melanoma oncogene BrafV600E. Our findings show that Mitf knockdown in melanocytes exhibit reduced proliferation regardless of the BrafV600E oncogene. Furthermore, our results showed differential gene expression of cell cycle regulators with and without the BrafV600E oncogene. The expression of Cdk2, a G1-S cell cycle promoter, is effectively reduced in the melanocytes, both with and without the BrafV600E oncogene. Contrarily, the expression of Cdkn2b, a G1 cell cycle inhibitor, was reduced in melanocytes carrying only the MitfK243R mutation but was increased in expression in the added presence of the BrafV600E mutation. Our results suggest that, like in melanoma, Mitf is involved in regulating the expression of cell cycle genes in melanocytes. The cell lines generated in this project will be an important tool for investigating for the first time the exact role of Mitf during melanocyte development. For example, they can be used to determine which genes are under direct regulation of Mitf and which are indirectly regulated by this transcription factor by investigating gene expression over time. This is therefore a very important tool for further investigations into the role of Mitf in melanocytes.
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