Biology of cancer, lecture 2 tumor viruses,oncogenes,tsgs
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Transcript of Biology of cancer, lecture 2 tumor viruses,oncogenes,tsgs
Adapted from The Biology ofCancer
First Edition
Chapter 3, 4 & 7
Copyright © Garland Science 2007
Robert A. Weinberg
Karobi Moitra (Ph.D)Karobi Moitra (Ph.D)NCI Frederick , NIHNCI Frederick , NIHCancer Inflammation ProgramCancer Inflammation ProgramHuman Genetics SectionHuman Genetics SectionFrederick MDFrederick MD..
Tumor VirusesOncogenes &Tumor Supressor genes
Figure 3.1 The Biology of Cancer (© Garland Science 2007)
Peyton Rous and Rous Sarcoma Virus (RSV)
1910 1966
Figure 3.2 The Biology of Cancer (© Garland Science 2007)
1909 Rous’s Protocol for inducing breast sarcomas in chicken
Viruses can cause cancer in chickens !
Figure 3.4a The Biology of Cancer (© Garland Science 2007)
The Virion (virus particle) of RSV and other related viruses:RNA viruses (retroviruses) can cause cancer
Figure 3.19 The Biology of Cancer (© Garland Science 2007)
Structure of the RSV genome
ALV = Avian leukosis virus Oncogene
Figure 3.4a The Biology of Cancer (© Garland Science 2007)
The Virion (virus particle) of RSV and other related viruses:RNA viruses (retroviruses) can cause cancer
Figure 3.4b The Biology of Cancer (© Garland Science 2007)
Murine (mouse) Leukemia Virus particles budding from an infected cell
Figure 3.7a The Biology of Cancer (© Garland Science 2007)
Normal cells can be converted into tumor cells (transformation)
Figure 3.5 The Biology of Cancer (© Garland Science 2007)
An RSV induced Foci
Normal cells can be converted into tumor cells (transformation) :RSV can transform infected cultured cells (in a petri dish)
CALTECH:Dulbecco,Rubin & Temin
Figure 3.9a The Biology of Cancer (© Garland Science 2007)
DNA Viruses can also induce cancer
Shopes virus Richard Shope
Figure 3.9b The Biology of Cancer (© Garland Science 2007)
HPV = Human papilloma virus - A DNA tumor virus
Genes and Cancer
Chromosomesare DNAmolecules
Heredity
RadiationChemicals
Viruses
Chemicals (e.g., from smoking), radiation, viruses, andheredity all contribute to the development of cancer by
triggering changes in a cell’s genes
Normal cellular genes with the potential to become oncogenesare called proto-oncogenes
Oncogenes or tumor genes are genes with potential properties for theinduction of neoplastic transformation
(either in natural or experimental conditions)
(Duesberg 1980)
Receptor
Normal Growth-Control Pathway
DNA
Cell proliferation
Cell nucleus
Transcriptionfactors
Signaling enzymes
Growth factor
Proto-Oncogenes and Normal Cell Growth
Oncogenes are related to normal genes called proto-oncogenes that encode components of the cell’s normalgrowth-control pathway. Some of these components are growth factors, receptors, signaling enzymes, andtranscription factors. Growth factors bind to receptors on the cell surface, which activate signaling enzymesinside the cell that, in turn, activate special proteins called transcription factors inside the cell’s nucleus. Theactivated transcription factors “turn on” the genes required for cell growth and proliferation.
Mutated/damaged oncogene
Oncogenes accelerate cell growth and division
Cancer cell
Normal cell Normal genes regulate cell growth
Oncogenes are genes whose PRESENCE incertain forms and/or overactivity canstimulate the development of cancer.
Oncogenes or tumor genes are genes with potential properties for theinduction of neoplastic transformation
(either in natural or experimental conditions)
(Duesberg 1980)
The word oncogene comes from the word ‘onkos ‘ meaning tumor
When an oncogene becomes activated it mightcause cancer
Proto-oncogene -> oncogene -> other steps -> cancer
Activation of Oncogenes
1. Mutation
a. Insertional mutagenesis
b. Point mutagenesis
2. Amplification
3. Translocation
Mutation : A mutation is a permanent change inthe DNA sequence of a gene. Mutations in agene's DNA sequence can alter the amino acidsequence of the protein encoded by the gene.
Figure 3.23b The Biology of Cancer (© Garland Science 2007)
ALV provirus may become integrated with the c-myc oncogene
ALV switches on c-myc
1a. Insertional Mutagenesis
1b. Mutagenesis of oncogenes
Altered polypeptides produced by mutant oncogenes could berelated to the origin of some human tumors
Activation of oncogenes
Figure 4.10 The Biology of Cancer (© Garland Science 2007)
Mutation responsible for H-ras oncogene activtion
Human bladder cancer oncogene - 12th codon of H-ras ,mutation converts glycine codon to valine codon
Activation of oncogenes
Figure 4.11a The Biology of Cancer (© Garland Science 2007)
The N-myc gene is often amplified in human childhoodneuroblastomas
FISH - showing amplification of N-myc to produces HSR’shomogeneous staining regions(chromosome 2)
Activation of oncogenes
Activation of oncogenes
3. Translocation
A karyotype is the number and appearanceof chromosomes in the nucleus of a
eukaryote cell
A chromosome translocation is a chromosomeabnormality caused by rearrangement of partsbetween nonhomologous chromosomes. A genefusion may be created when the translocationjoins two otherwise separated genes, theoccurrence of which is common in cancer.
Figure 4.13a The Biology of Cancer (© Garland Science 2007)
Burkitts lymphoma t(8;14) the c-myc gene is placed under the control of the enhancer sequence of an immunoglubulin gene
Figure 4.15a The Biology of Cancer (© Garland Science 2007)
Reciprocal translocations between human Chr 9 (abl) and 22 (bcr)
Fusion protein
Bcr-abl oncogene formation gives rise to acute lymphocytic leukemia (ALL),chronic myelogenous leukemia (CML) or chronic
neutrophillic leukemia (CNL)
Activation of Oncogenes
1. a. Insertional mutagenesis
b. Point mutagenesis
2. Amplification
3. Translocation
Tumor Suppressor Genes
Tumor suppressor genes are normal genes whose ABSENCE can lead to cancer
i.e. Tumor suppressor genes protect the cell
Tumor Suppressor Genes - Tumor suppressor genes are normal genes whose ABSENCE can lead to cancer
i.e. Tumor suppressor genes protect the cell
Normal genes prevent cancer
Remove or inactivatetumor suppressor genes
Mutated/inactivatedtumor suppressor genes
Damage to both genes leads to cancer
Cancer cell
Normal cell
If a pair of tumor suppressor genes are eitherlost from a cell or inactivated by mutation,their functional absence might allow cancerto develop
Tumor Suppressor GenesAct Like a Brake Pedal
Tumor SuppressorGene Proteins
DNACell nucleus
Signalingenzymes
Growth factor
Receptor
Transcriptionfactors
Cell proliferation
Tumor suppressor genes are a family of normal genes that instruct cells to produce proteins that restrain cell growth and division. Since tumorsuppressor genes code for proteins that slow down cell growth and division, the loss of such proteins allows a cell to grow and divide in anuncontrolled fashion. Tumor suppressor genes are like the brake pedal of an automobile. The loss of a tumor suppressor gene function is likehaving a brake pedal that does not function properly, thereby allowing the cell to grow and divide continually.
p53 Tumor Suppressor ProteinTriggers Cell Suicide
Normal cell Cell suicide(Apoptosis)
p53 protein
Excessive DNA damage
One particular tumor suppressor gene codes for a protein called “p53” that can trigger cell suicide (apoptosis). In cellsthat have undergone DNA damage, the p53 protein acts like a brake pedal to halt cell growth and division. If the damagecannot be repaired, the p53 protein eventually initiates cell suicide, thereby preventing the genetically damaged cellfrom growing out of control.
Figure 7.4b The Biology of Cancer (© Garland Science 2007)
Retinoblastoma occurs when pRB is mutated (inactivated)or sometimes deleted
Figure 7.10 The Biology of Cancer (© Garland Science 2007)
Deletion of a part of Chromosome 13 in a retinoblastoma patient
Tumor suppressor genes are normal genes whose ABSENCE can lead to cancer
Oncogenes or tumor genes are genes with potential properties for theinduction of neoplastic transformation either in natural
or experimental conditions (Duesberg 1980)