Chapter 3: Tumor VirusesPeyton Rous discovers a chicken sarcoma virus (1911)
Rous sarcoma virus is discovered to transform infected cells in culture
Retrovirus
Renato Dulbecco (California IT)
Harry Rubin/ An RSV-induced focus
Howard Temin/ Transformation
Howard Temin, 1975 Nobel Prize with David Baltimore
Transformed cells forming foci.
The continued presence of RSV is needed to maintain transformation
Shope papillomavirusViruses containing DNA molecules are also able to induce cancer
SV40 virus
Permissive hostPolio vaccine (Sabin and Salk) contaminated with SV40 from 1955 to 1963
Anchorage-independent growth
Nude mice
Tumor viruses induce multiple changes in cell phenotype including acquisition of tumorigenicity
Transformation
Tumor virus genomes persist in virus-transformed cellsby 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 protooncogenesby inserting their genomes adjacent to these cellular genes
Some retroviruses naturally carry oncogenes
Insertional mutagenesis
ALV/ lack acquired oncogenesB-call lymphomas induced by ALV
HTLV-I/ tax (transcription activator)
Chapter 4: Cellular Oncogenes
Can cancers be triggered by the activation ofendogenous retroviruses?
Transfection of DNA provides a strategy for detecting nonviral oncogenes
Transfection
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.
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Amplification of the erbB2/HER2/neu oncogene in breast cancers
Fluorescence in situ hybridization
Kaplan-Meier plot
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 neuroblastomaGenemycMYC
ProteinMycMYC
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
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