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BIOLOGY 2C03 (138)
Joe Kim (16)
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Module 12(1-2) - Oncogenes - April 4-5 - BIO 2C03.docx
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Department
Biology
Course
BIOLOGY 2C03
Professor
Joe Kim
Semester
Winter

Description
BIO 2C03 2013 Module 12 Lecture 1 – Cancer Genetics; Oncogenes (April 4) Chapter 23 Useful Definitions  Cancer o Clinical disease of cellular proliferation o Abnormal mass of tissue, the growth of which exceeds and is uncoordinated with the surrounding tissue o Behaves in an independent manner  Benign o Slow growing, may stop or regress o Usually exhibited differentiated characteristics o Often encased by a fibrous capsule o Non-invasive into the surrounding tissue  Malignant o Variable rates of growth o Variable levels of differentiation, poorly differentiated tumors are often the most aggressive o Invasive into surrounding tissues, a process that often requires the breakdown of extracellular matrices – by secretion of proteolytic enzymes o Potential to metastasize o Often angiogenic  Major Classes of Human Cancers o Carcinomas – arising from cells of the epithelium; account for 90% of human cancer  Eg/ colon, breast, prostate, lung o Sarcomas – arising from cells of supporting (connective) tissues  Eg/ bone, muscle, fibroblast o Leukemia and Lymphomas – arising from cells of the hematopoietic system Properties of Transformed (Cancer) Cells  Altered morphology and increased motility  “proliferation without constraints” (eg/ at low concentrations of growth factors, loss of contact inhibition, anchorage-independent proliferation)  Immortalization  block to differentiation  escape from apoptosis (programmed cell death)  Tumorigenic (form tumors in animals)  capacity to invade surrounding tissues and metastasize  Loss of Contact Inhibition – focus formation assay  Loss of Anchorage Dependence – colony formation assay 1 BIO 2C03 2013  Genes and Cancer o There are three classes of genes which are found mutated in cancer  Oncogenes (mutation on proto-oncogene) – behave as gain of function mutations; their wild type function have a positive effect on cell proliferation (promotes)  Tumor suppressors – mutations are lack of function recessive alleles; the wild type function is required to prevent cell proliferation (inhibitory)  Mutator Genes – required to maintain genomic stability; absence causes genomic instability and accumulation of mutations Discovery of v-Src  Historical Events Associated with the Discovery of Genes Involved in Cancer o By early 1900’s  Association of tobacco and coal with lung cancer  Description of rare families with hereditary cancer  Cell-free filtrates (viruses) can transmit leukemia and other cancers in animals o 1911 – Peyton Rous discovers Rous sarcoma virus – an avian retrovirus that causes the formation of sarcoma in chickens, the virus was propagated by inoculating healthy chickens with extracts from tumors o With the advent of tissue culture, it became possible to isolate cancer-causing viruses, propagate them in culture and study their effects on cultured cells o The study of these viruses eventually led to the discovery of oncogenes – genes that promoted the formation of tumors or transformation of cell in culture  Characterization of the Rous sarcoma virus (RSV) and the v-Src Oncogene  Why study the oncogenes of retroviruses? o Viral oncogenes have cellular counterparts, the proto-oncogenes, that can also become oncogenic and cause cancer o Eg/ the cellular Src gene is often mutated and oncogenic in advanced colon carcinomas o The cellular Ras gene is often mutated in bladder carcinomas (Weinberg, 1980)  Definitions o v-Src = Viral Src (transforming) o c-Src = cellular Src (non-transforming) o activated Src = Oncogenic (mutated) cellular Src (transforming)  Function of Oncoproteins o A function controlling cell proliferation; i.e. it is a component of a signaling pathway controlling cell proliferation o Eg/  Growth factors  Receptors for a growth factor  Cytoplasmic signaling proteins  Transcription factors  Cell cycle regulators o PS Src is a signaling tyrosine kinase that associates with cell surface receptors and induces a cascade of signaling reactions leading to the stimulation for DNA synthesis and cell division Proto-Oncogenes Oncoproteins as Components of Signaling Pathways  Bcl-1 B-cell leukemia/lymphoma 1: = Cyclin D1 2 BIO 2C03 2013  Example of a signaling pathway o Eg/ receptors for the epidermal growth factor - EGF  How do signaling pathways control cell proliferation o Signaling pathways, controlled by oncoproteins, regulate the expression or activity of a component of the cell cycle machinery o Eg/ oncoproteins like v-ErbB (=EGF-R) v-Src or v-Ras controls the expression of cyclin D1, a positive regulator of the cell cycle 3 BIO 2C03 2013 Mechanisms of Oncogenic Activation  How do Oncogenes appear?  What is the difference between a proto-oncogene and an oncogene? o Oncogenes can transform cells; proto oncogenes cannot  Why do oncogenes transform? o Two major principles/processes  Function/regulation is altered – the protein is activated at all times  Expression is elevated o In all cases, the result is a gain of function o Oncogenes act in a dominant matter  Changes of Structure/Function (point mutations) o Eg/ activated Ras in bladder carcinoma  A single point mutation in the Ras proto oncogene (Gly 12 Val) generated a constitutively active form of Ras that always signals and induces cell proliferation  Therefore, the wild type form of Ras (encoding Gly at position 12) is the proto-oncogene while the mutated or activated form of Ras (encoding Val at position 12) is the oncogene o Eg/ H-Ras (FYI)  Changes in protein regulation or activation are the result of point mutations, small deletions etc  Over-expression can be obtained by: A. Transduction in a retrovirus  Where do retroviral oncogenes come from  Retroviral oncogenes are derived from cellular proto-oncogenes  Proto-oncogenes can be acquired (“trapped”) by retroviruses  Proto-oncogenes were likely trapped as mRNA molecules and integrated in the RNA genome of retroviruses during evolution  Proto-oncogenes, trapped by a retrovirus, become oncogenic (i.e. oncogenes) following mutation and over- expression  Viral oncogenes are derived from cellular genes or proto-oncogenes 4 BIO 2C03 2013  How was c-Src captured by a retrovirus?  Oncogenic activation of c-Src following transduction B. Promoter insertion  The Avian Leukosis Virus (ALV) causes leukemia after a period of latency; Oncogenic Activation by promoter insertion  ALV does not encode an oncogene but transform cells by promoter insertion near a proto-oncogene  Eg/ ALV & Myc (Myc is a transcription factor)  Induction of leukemia following infection by ALV is always preceded by a period of latency; because of two reasons: i. Integration of ALV is random and therefore it takes several rounds of infection to obtain integration near a proto-oncogene such as Myc(low probability) o Once integrated near Myc, ALV drives the expression of Myc to high levels, inducing cell transformation; at this point the aberrantly expressed Myc is oncogenic i.e. Myc has become an oncogene 5 BIO 2C03 2013 ii. The leukemic cell transformed by Myc must divide several times to cause the leukemia i.e. the population the leukemic cells must expand considerably C. Gene amplification  Eg/ N-Myc and neuroblastomas  Amplification results ni tandem arrays of N-Myc genes  Amplification of N-Myc over 10 copies correlates with poor prognosis  EFS = event free survival D. Chromosomal Rearrangement/Translocation (a proto-oncogene is translocated near a strong promoter/enhancer on the chromosome increasing its expression)  Eg/ c-Myc and Burkitts lymphomas Oncogene Cooperation  Myc and Ras cooperate in the transformation of primary Rat Embryo Fibroblasts  Oncogenes cooperate by altering/targeting different cellular functions or processes that are required for full transformation of the cell  Focus formation assay Myc and Ras also cooperate in vivo in a tumor model Lecture 2 – Cancer Genetics; Tumor Suppressor Genes (April 5) 6 BIO 2C03 2013 Chapter 23 Tumor Suppressor Genes  Tumor Suppressor – genes whose loss-of-function promotes tumor formation  Tumo
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