oncogenes
TRANSCRIPT
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What Is Cancer?
•Cancer is a large group of diseases (over 200) characterized by uncontrolled growth and spread of abnormal cells.*
*American Cancer Society, Cancer Facts and Figures 2005
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•At cellular level • Excessive cellular proliferation•Uncoordinated growth• Tissue infiltration
•At molecular level •Disorder of growth regulatory genes
Carcinogenesis
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Normal Cells Vs. Cancer Cells
• Cancer cells:• Lose control over growth
and multiplication
• Do not self-destruct when they become worn out or damaged
• Crowd out healthy cells
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NORMAL CELLgrowth factorgrowth factor receptor
signal transduction
activation of transcription
cytoplasm
nucleusDNA
RNA
Carcinogenesis
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NEOPLASTIC (malignant) CELLS
Increasein growth factors
Increasein growth factorreceptors
Increase in signal transduction
Increase in activation of transcription
- Disturbed processes of mitosis and protein synthesis
Carcinogenesis
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Properties of cancer cells
•1: self-sufficient in growth signals•2: insensitive to anti-growth signals•3: stimulate local angiogenesis•4: evade apoptosis
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Classes of Genes Involved in the Development of Tumour• Non lethal genetic damage is the initiating
event in carcinogenesis.There are principally four classes of genes which when affected by such changes , can result in the development of a tumour
1. Proto-oncogenes 2. Tumour suppressor gene3. Genes involved in DNA repair4. Genes involved in apoptosis
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Oncogenes
• Oncogene: “onco” (cancer) gene
• 1989 Nobel Prize in Medicine or Physiology: The Discovery of the Cellular Origin of Retroviral Oncogenes• J. Michael Bishop (UCSF)• Harold Varmus (UCSF)
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Oncogenes Cont’d• Proto-oncogenes: normal cellular genes usually
involved in cell growth and/or cell division
• Oncogenes: a proto-oncogene that has been activated by mutation or overexpression. Results in a dominant gain of function phenotype• Growth Factors, Growth Factor Receptors,
G-proteins, Kinases, Gene Regulatory Proteins
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Common Human Oncogenes
The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000
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How are oncogenes activated?
• Point mutation-eg. K-ras, • Amplification-eg. N-myc, MDM2,
Her2/neu/ErbB2• Chromosome translocation-eg. c-myc, bcr-
abl• Overexpression due to DNA demethylation
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List of carcinogens
Chemical• Asbestos• Arsenic• Chromium• Polyaromatic hydocarbons• dichlorodiphenyl-
trichloroethane (DDT)
Physical• Gamma radiation• UV light• Radon• X-rays• Viruses*
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Viruses and cancer
• Viruses account for 15% of all cancers• DNA viruses• Epstein-Barr virus• Human papilloma virus• Hepatitis B virus
• RNA viruses• HIV-1• HTLV-1• HTLV-2
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Tumor Suppressor Genes• Genes that are normally involved in the inhibition
of cell growth and proliferation. • Two Hit Hypothesis: Tumor suppressor genes act in
a recessive manner• Need loss of both alleles to progress towards
cancer
Molecular Biology of the Cell. Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter. New York and London: Garland Science; c2002
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Common Human Tumor Suppressor Genes
The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000
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Mechanisms of tumor suppressor gene inactivation
• Deletion• Point mutation• Mutation followed by duplication• Loss of heterozygosity• DNA methylation• Post-translational mechanism-binding to DNA
viral oncoproteins
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Retinoblastoma (Rb) Tumor Suppressor Gene
Rb prevents E2F transcription factor from transcribing genes inappropriately
Loss of Rb allows for unregulated gene transcription
The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000
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Genetics of Retinoblastoma
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p53 Tumor Suppressor Gene
p53 is the single mostcommon target for geneticinsults leading to cancer
DNA damage stabilizes p53and allows for p53 accumulation
p53 induces p21 (CDKN1A, CIP1, WAF1) to cause cell cycle arrestThe state in which p53 is mutated is referred to as Li Fraumani syndrome
Robbins & Cotran Basic Pathology 7th ed
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Multiple Hit Hypothesis
Cancer is due to an accumulation of genetic insults (oncogeneactivation, loss of tumor suppressor genes)
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Oncogene Addiction Hypothesis
• Cells become addicted to persistent oncogene activity for proliferation• Become unresponsive to any other
mitogenic (growth) stimuli
• Turn off MYC and cells can respond to other stimuli• Tumor cells begin to become more
normal
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MYC Oncogene Addiction in Hepatocellular Carcinoma
Felsher, et al.
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MYC Inactivation Uncovers Pluripotent Differentiation and Tumor Dormancy in Hepatocellular CancerShachaf CM, Kopelman AM, Arvanitis C, Karlsson A, Beer S, Mandi S, Bachman MH, Borowsky AD, Ruebner B, Cardiff RD, Yang Q, Bishop JM, Contag CH, Felsher DW. Nature. Vol431, 2004.
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The Concept of Gene Therapy