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thesis - Thesis for doctoral degree(Ph.D 2007 Thesis for...

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Thesis for doctoral degree (Ph.D.) 2007 Malihe Eskandarpour Thesis for doctoral degree (Ph.D.) 2007 Malihe Eskandarpour Molecular Genetics of Cutaneous Malignant Melanoma Molecular Genetics of Cutaneous Malignant Melanoma
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Karolinska Institutet, Department of Oncology-Pathology Stockholm, Sweden Molecular Genetics of Cutaneous Malignant Melanoma Malihe Eskandarpour Stockholm 2007
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2007 Gårdsvägen 4, 169 70 Solna Published and printed by Doctoral Dissertation © Malihe Eskandarpour, 2007 Karolinska Institutet Department of Oncology-Pathology Stockholm, Sweden
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To My parents Jalal and Parvin & Shahryar and Armin
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iv List of publications The thesis is based on the following publications, which are referred to in the text by Roman numerals as follows: Ι . Eskandarpour M , Hashemi J, Kanter L, Ringborg U, Platz A, Hansson J. Frequency of UV-Inducible NRAS Mutations in Melanomas of Patients With Germline CDKN2A Mutations. Journal of the National Cancer Institute 2003; 95(11):790-798. Ι Ι . Eskandarpour M, Kiaii S, Zhu C, Castro J, Sakko AJ, Hansson J. Suppression of Oncogenic NRAS by RNA Interference Induces Apoptosis of Human Melanoma Cells . International Journal of Cancer 2005; 115, 65-73. Ι Ι Ι . Eskandarpour M , Huang F, Reeves KA, Clark E, Hansson J. Oncogenic NRAS has a Pivotal Role in the Malignant Phenotype of Human Melanoma Cells. Submitted for publication. All published papers are reprinted with permission from the corresponding publishers.
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1 Table of contents List of Publications ................................................................................................ IV Table of Contents ..................................................................................................... 1 Abbreviations ........................................................................................................... 2 Abstract .................................................................................................................... 3 Cutaneous Malignant Melanoma ............................................................................ 5 Melanoma Tumor Progression ............................................................................... 5 Melanoma Risk Factors ........................................................................................... 7 Pathways Involved in Melanoma Biology ............................................................... 8 RAS Signaling Pathway ....................................................................................................................... 9 RAS-RAF-ERK SIGNALLING ..................................................................................................................... 10 RAS-PI3K-AKT SIGNALING ...................................................................................................................... 11 RAS-RAL SIGNALING ................................................................................................................................ 11 OTHER EFFECTORS OF RAS SIGNALING PATHWAY ..................................................................................... 12 RB and p53 Pathways ............................................................................................ 13 Mutations in Oncogenes and Suppressor Genes in Melanoma ............................ 13 Chromosomal Abnormalities in Melanoma ......................................................... 17 Susceptibility Genes in Melanoma ........................................................................ 18 Cooperation of RAS and CDKN2A ...................................................................... 20 RAS and Cell Cycle Regulation ............................................................................ 21 RAS and Cell Invasion .......................................................................................... 22 RAS in Differentiation, Growth Arrest and Senescence ...................................... 23 Oncogenic RAS and Human Cancer ..................................................................... 24 Targeting the RAS Oncogenes ....................................................................................................... 25 Aims ....................................................................................................................... 27 Results and Conclusions ................................................................................................................... 28 P APER Ι ..................................................................................................................................................... 28 P APER Ι Ι ................................................................................................................................................... 29 P APER Ι Ι Ι ................................................................................................................................................. 30 Future Perspectives ............................................................................................... 32 Acknowledgments .................................................................................................. 33 References ................................................................................................................................................ 36
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2 Abbreviations ARF alternative reading frame bFGF basic fibroblast growth factor CDK cyclin dependent kinase CDKN2A cyclin dependent kinase inhibitor 2A CGH comparative genomic hybridization CIP1 CDK interacting protein 1 (CDKN1A) CMM cutaneous malignant melanoma CPD cyclobutane pyrimidine dimmer ERK extracellular signal regulated kinase FAK focal adhesion kinase FTI farnesyltransferase inhibitors GEF guanine nucleotide exchange factor GPCR G-protein-coupled receptor HDM2 human double minute 2 MAPK mitogen activated protein kinase MC1R melanocortin 1 receptor MEK MAP-ERK kinase MLCK myosin light chain kinase MMP matrix metalloprotease NF- κ B nuclear factor-kappa B NMA neuromedin A Nore 1 novel ras effector 1 PI3K phosphoinositide 3 kinase PIP3
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