thesis - Thesis for doctoral degree(Ph.D 2007 Thesis for doctoral degree(Ph.D 2007 Molecular Genetics of Cutaneous Malignant Melanoma Molecular Genetics

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

This preview has intentionally blurred sections. Sign up to view the full version.

View Full Document

Karolinska Institutet, Department of Oncology-Pathology Stockholm, Sweden Molecular Genetics of Cutaneous Malignant Melanoma Malihe Eskandarpour Stockholm 2007

2007 Gårdsvägen 4, 169 70 Solna Published and printed by Doctoral Dissertation © Malihe Eskandarpour, 2007 Karolinska Institutet Department of Oncology-Pathology Stockholm, Sweden

This preview has intentionally blurred sections. Sign up to view the full version.

View Full Document

To My parents Jalal and Parvin & Shahryar and Armin

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.

This preview has intentionally blurred sections. Sign up to view the full version.

View Full Document

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

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