The Role of Ultraviolet Radiation in Molecular Pathways to Melanoma

Hacker, Elke (2006). The Role of Ultraviolet Radiation in Molecular Pathways to Melanoma PhD Thesis, School of Medicine, University of Queensland.

       
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Author Hacker, Elke
Thesis Title The Role of Ultraviolet Radiation in Molecular Pathways to Melanoma
School, Centre or Institute School of Medicine
Institution University of Queensland
Publication date 2006
Thesis type PhD Thesis
Supervisor Dr Graeme Walker
Abstract/Summary A great deal of cancer research is aimed at describing the precise mechanisms that allow cells to become transformed. Many genes have been associated with melanoma and the majority of the functions of these genes pertain to three pathways Ras/Raf/MAPK, Ink4a/Cdk4-cyclin/pRb and ARF/Mdm2/p53. Over-expression of Hras in melanocytes, combined with a single neonatal UVR dose is sufficient to induce melanoma in pigmented mice. These lesions were small in situ cutaneous melanomas. To assess the role of the pRb pathway in melanoma mice, over expressing Hras were combined with activated Cdk4 mutants. These animals develop melanoma spontaneously, with a penetrance of 58%, which rose to 83% after neonatal ultraviolet radiation (UVR). Furthermore, the entire UVRtreated cohort that developed melanoma had multiple cutaneous lesions and 92% had metastatic tumours. In this model Hras activation alone is sufficient to predispose melanocytes to UVR-induced transformation, while mutant Cdk4 is more important for tumour progression, producing larger more aggressive, metastatic melanomas. To further assess the Ink4a/Cdk4-cyclin/pRb pathway in this disease a melanocytespecific deletion of the Rb1 gene was constructed. This model allowed for the culturing of Rb1-null melanocytes. Rb1-null melanocytes were studied and found to proliferate more rapidly than controls and to have a decreased requirement for mitogens. Expression arrays were performed to identify differences between the small in situ TPras lesions and those more aggressive Cdk4[superscript]R24C/R24C/TPras melanomas. We observed up regulation of Tcfeb, Ednrb, Tcfap2b and Gpr155 and down regulation of Plagl1 in Cdk4[superscript]R24C/R24C/TPras lesions. The overlay of expression and aCGH analysis showed dysfunction of various genes that are involved in regulating p53 and DNA repair pathways in the Cdk4[superscript]R24C/R24C/TPras tumours (Plagl1, Abcc10, Hsp90aa1 and Htatip). We also observed aberrations of several genes that regulate p21 (E2F2 and Htatip) and identified several potential markers of melanoma progression (Pax7, Dpp3, cdc42, Fgf22, Nme2, Esm1, Ednrb, Mum1 and Notch4). We also identified several genetic changes in Cdk4[superscript]R24C/R24C/TPras tumours that were specific to either UVR-induced or spontaneously derived lesions and identified a number of candidate genes (Hsp90aa1, Gzmk, Esm1, Bop1, Rapgef3, Htatip and Dpp3). This study has identified numerous novel candidate genes and also confirmed the importance of various melanoma-associated genes in this disease.

 
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