Chapter 3: Tumor Viruses Peyton Rous discovers a chicken sarcoma virus (1911) Rous sarcoma virus is discovered to transform infected cells in culture Renato Dulbecco (California IT) Harry Rubin/ An RSV-induced focus Howard Temin/ Transformation Howard Temin, 1975 Nobel Prize with David Baltimore Retrovirus Transformed cells forming foci. The continued presence of RSV is needed to maintain transformation Viruses containing DNA molecules are also able to induce cancer Shope papillomavirus Permissive host Polio vaccine (Sabin and Salk) contaminated with SV40 from 1955 to 1963 SV40 virus Transformation Tumor viruses induce multiple changes in cell phenotype including acquisition of tumorigenicity Anchorage-independent growth Nude mice Tumor virus genomes persist in virus-transformed cells by becoming part of host-cell DNA Almost all cervical cancer found HPV genome The life cycle of an RNA tumor virus like RSV. A version of the src gene carried by RSV is also present in uninfected cells Structure of the RSV genome The construction of a src-specific DNA probe. RSV exploits a kidnapped cellular gene to transform cells Proto-oncogene The vertebrate genome carries a large group of protooncogenes The vertebrate genome carries a large group of protooncogenes Slowly transforming retroviruses activate protooncogenes by inserting their genomes adjacent to these cellular genes Some retroviruses naturally carry oncogenes HTLV-I/ tax (transcription activator) Insertional mutagenesis ALV/ lack acquired oncogenes B-call lymphomas induced by ALV Chapter 4: Cellular Oncogenes Can cancers be triggered by the activation of endogenous retroviruses? Transfection Transfection of DNA provides a strategy for detecting nonviral oncogenes Transformation of mouse cells by human tumor DNA Oncogenes discovered in human tumor cell lines are related to those carried by transforming retroviruses × Homology between transfected and retroviral oncogenes. Amplification of the erbB2/HER2/neu oncogene in breast cancers Kaplan-Meier plot Fluorescence in situ hybridization Elevated expression of 17q genes together with overexpression of rebB2/HER2 Nonrandom amplifications and deletions of chromosomal regions Proto-oncogenes can be activated by genetic changes affecting either protein expression or structure Cloning of transfected human oncogenes Localization of an oncogene-activating mutant transfection-focus assay Mutation responsible for H-ras oncogene activation Concentration of point mutations leading to activation of the K-ras oncogene Variations on a theme: the myc oncogene can arise via at least three additional distinct mechanisms N-myc amplification and neuroblastoma Gene myc MYC Protein Myc MYC Burkitt’s lymphoma incidence in Africa Chromosomal translocations in Burkitt’s lymphoma Translocations liberating an mRNA from miRNA inhibition A diverse array of structural changes in proteins can also lead to oncogene activation Deregulated firing of growth factor receptors Formation of the bcr-abl oncogene