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Midterm -Chapter 4,11,12,13,14 -Material only covered during the class - slide No 23-26 from lecture 12 will not be covered in the midterm -10/24 (Mon), 4:00-6:00pm 창의관 311호 -Office hour : 10/22 from 10am to 12pm 생명과학과 (building E6-3, Rm 3207) Midterm Types of Questions No of questions Note Point s Multiple choices 40 (1pt/Q) 40 Fill in the blank or T/F 10 (More than 1 blank /Q) 40 Only in English Short answer 4 (2.5 pts/Q) Terminologies should 10 be in English Essay 2 (5 pts/Q) Terminologies shoud be in English Total 56 questions 10 100 Chapter 14 Mutation, DNA repair, and Cancer Causes of Cancers - Genetic inheritance e.g., BRCA1 - Exposure to external carcinogens e.g., UV, burnt food, smoking Carcinogens cause alterations in DNA sequences or structure => Affect expression of genes critical in maintaining normal cell growth - Or in combination Two classes of genes that can cause a cancer when mutated Mutations that cause Hyperactivation of oncogenes Loss of functions of tumor suppressor genes Uncontrolled cell growth Tumor Two classes of genes that can cause a cancer when mutated Two classes of genes that can cause a cancer when mutated How proto-oncogenes become oncogenes? How proto-oncogenes become oncogenes? 1) Missense mutation 2) Gene amplification 3) Chromosomal translocations How proto-oncogenes become oncogenes? How proto-oncogenes become oncogenes? 4) Retroviral insertions Viral DNA may insert into a host chromosome => a viral promoter and response elements are next to a proto-oncogene => the overexpression of the proto-oncogene Two classes of genes that can cause a cancer when mutated 1) Onogenes : Genes that have the potential to cause a cancer 2) Tumor suppressor genes : Genes that protect a cell from forming a cancer Tumor suppressor genes 1) Normal role : to prevent cancerous growth 2) Encode proteins with one of two functions A) Maintain the integrity of the genome by monitoring and/or repairing alterations in the genome e.g. Checkpoint proteins Tumor suppressor genes Checkpoint proteins : Check integrity of genome before cells progress to the next step of cell cycle If abnormally detected => stop the cell division e.g., p53 : DNA damage sensor promote DNA repair, prevent cell cycle progression about 50% of all human cancers are associated with defects in this gene Tumor suppressor genes 1) Normal role : to prevent cancerous growth 2) Encode proteins with one of two functions A) Maintain the integrity of the genome by monitoring and/or repairing alterations in the genome e.g. Checkpoint proteins B) Negative regulators or inhibitors of cell division without a proper signal e.g., Retinoblstoms (RB) Tumor suppressor genes Retinoblastoma Retinoblastoma: Cancer in Retina (diagnosed at an avg of 18 months) Retina Tumor suppressor genes •The mechanism of Rb in Normal celll Transcription activator that promotes expression of proteins Involved in DNA synthesis Cell growth signal Rb becomes phosphorylated Late G1 Cell cycle progression Transcription of Enzymes for DNA synthesis Tumor suppressor genes Loss of Rb function 1) Deletion 2) Inactivating mutation Transcription of Enzymes for DNA synthesis In the absence of signal G1 to S Tumor suppressor genes •The mechanism of Rb mutation in Retinoblastoma Loss of Rb function One copy of Rb gene is lost Remaining copy (inherited) Undergoes mutation Tumor suppressor genes Loss of tumor-suppressor gene function 3 common ways Mutation to inactivate its function loss Chromosome that carries one or more tumor-suppressor genes Abnormal methylation of CpG islands near promoter regions cause compaction of chromatin => repress expression of tumor suppressor 19 Cancer progression Hyperactivation of oncogenes Loss of functions of tumor suppressor genes •Uncontrolled cell growth Tumor Genetic/epigenetic changes Metastasis (spread to other organs) Accounts for over 90% of cancer related-death The Hallmarks of Cancer - Genetic inheritance - Exposure to external carcinogens Functional gain of Oncogenes Functional loss of Tumor suppressor genes Tumor cells Normal cells Tight control Tumor cells The Hallmarks of Cancer External carcinogens Genetic inheritance Deregulation of signaling pathways Cancer cell Common phenotypic traits The Hallmarks of Cancer Evading XIAP apoptosis Sustained angiogenesis Self-sufficiency FoxO1 In growth signal MDM2 AKT PI3K Tissue invasion & metastasis Survival/ Survival/ Proliferation Proliferation Insensitivity to antiGrowth signals Limitless replicative potential Modified from Luo et al Cell (2009) 136, 823-837 The Hallmarks of Cancer Sustained Angiogenesis Angiogenesis process The Hallmarks of Cancer Sustained Angiogenesis Angiogenesis in tumor Xenograft Implantation of human colorectal Cancer cells in to the skin of mouse The Hallmarks of Cancer Sustained Angiogenesis VEGF mediated signaling pathways VEGF VEGFR-2 Vascular Endothelial cell plasma membrane Binding of L Dimerization Subsequent signal transduction Angiogenesis The Hallmarks of Cancer Sustained Angiogenesis The role of VEGF in angiogenesis in tumor Tumors treated with VEGFR inhibitor