《医学遗传学》7年制课件Cancer Genetics.ppt

7．Mechanisms of Oncogenesis 7.2．Chromosome Theory Boveri T (1914) Abnormal fertilization of sea urchin eggs by two sperm cells causes unequal distribution of chromosomes in resulting daughter cells. 7．Mechanisms of Oncogenesis 7.2．Chromosome Theory Boveri T (1914) The unequal distributions of chromosomes could be the causal factors in tumor formation. 7．Mechanisms of Oncogenesis 7.2．Chromosome Theory Boveri T (1914) Tumor cells come from normal cells. Tumor cells are defective cells with chromosomal abnormality. The chromosomal aberrations are the causal factors in tumor formation. 7．Mechanisms of Oncogenesis 7.3．Two Mutation Theory Knudson (1971) Retinoblastoma (RB) The Nobel Prize in Physiology or Medicine 1989 J. Michael Bishop for his discovery of the cellular origin of retroviral oncogenes 4．Oncogene A gene that causes normal cells to change into cancerous tumor cells. Proto-oncogene: A gene that normally directs cell growth. 4．Oncogene 4.2．Categories of Oncogenes Growth factors Growth factor receptors Signal-transduction protein Transcription factor Apoptosis regulatory factor activating SRC, ABL, ROS, YES HRAS KRAS NRAS MAPKK MAPK CYTOPLASM NUCLEUS SIS, INT2, HST ERBB1, FMS, ERBA, KIT Cytoskeleton SRC、ABL、ROS、YES Cascade reaction MYC JUN, FOS DNA replication Transcription regulation EXTRACELLULAR Schematic of Oncogene 4．Oncogene 4.3．Mechanisms of Oncogene Activation 4.3.1．Mutation Point mutations/deletions/insertions Most characterized in transcription-regulating sequence (TRS). Frequent in Ras family 4．Oncogene 4.3．Mechanisms of Oncogene Activation 4.3.2．Gene Amplification Results from several rounds of unscheduled DNA synthesis occurring during a single cell cycle. Homogeneously staining region (HSR) Double minutes (DMs) Homogeneously staining region (HSR) Double Minutes (DMs) 4．Oncogene 4.3．Mechanisms of Oncogene Activation 4.3.3．Chromosomal Rearrangement Transcriptional activation Fusion gene (mosaic protein) Transcriptional activation Burkitt