Download Cancer

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
The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000
Ras and Raf oncogenes are constitutively active
persistant
MAPK signaling
unregulated gene transcription
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 and the Cell Cycle
MYC
Degradation of p27
(CDK inhibitory protein)
Increased activity of Cyclin/CDK complexes
Phosphorylation of inhibitory Rb protein
Increased activity of E2F
G1
S
Cells continue through cell cycle
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
The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000
Rb prevents E2F transcription factor from transcribing genes
inappropriately
Loss of Rb allows for unregulated gene transcription
p53 Tumor Suppressor Gene
p53 is the single most
common target for genetic
insults leading to cancer
DNA damage stabilizes p53
and 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 (oncogene
activation, 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.
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
+Dox
(MYC off)
-Dox
(MYC on)
-Dox
+Dox
(MYC on) (MYC off)
%Survival
+Dox
(MYC off)
QuickTime™ and a
TIFF (Uncompressed) decompres sor
are needed to see this picture.
-Dox
(MYC on)
Time (weeks)
MYC Inactivation Uncovers Pluripotent Differentiation and Tumor Dormancy in Hepatocellular Cancer
Shachaf 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.
MYC Inactivation Uncovers Pluripotent Differentiation and Tumor Dormancy in Hepatocellular Cancer
Shachaf 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.