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