Download - March 5, 2009
March 5, 2009
Lecture Outline
• Oncogenes
• Tumor Suppressor Genes
• Multiple Hit Hypothesis
• Oncogene Addiction Hypothesis
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)
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
Oncogene Activation
Molecular Biology of the Cell. Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter. New York and London: Garland Science; c2002
Ras/Raf Oncogenic Signaling
Ras and Raf oncogenes are constitutively active persistantMAPK signaling unregulated gene transcription
The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000
MYC Oncogene• Normal nondividing cells
– Myc levels are low but responsive to growth signals from the cellular environment
• Dividing cells– Myc levels constantly maintained at an
intermediate level throughout cell cycle• Oncogenic MYC
– Point mutation prevents MYC degradation allows for accumulation of high levels of MYC
– Increased transcriptional activity
MYC
Degradation of p27
Phosphorylation of inhibitory Rb protein
Increased activity of E2F
Cells continue through cell cycle
G1 S
Increased activity of Cyclin/CDK complexes
MYC and the Cell Cycle
(CDK inhibitory protein)
Common Human Oncogenes
The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000
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
Common Human Tumor Suppressor Genes
The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000
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
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 arrest
Robbins & Cotran Basic Pathology 7th ed
Multiple Hit Hypothesis
Cancer is due to an accumulation of genetic insults (oncogeneactivation, loss of tumor suppressor genes)
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
MYC Oncogene Addiction in Hepatocellular Carcinoma
Felsher, et al.
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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val
Time (weeks)
+Dox(MYC off)
-Dox(MYC on)
+Dox(MYC off)
-Dox(MYC on)
-Dox +Dox(MYC on) (MYC off)
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.