elo 174 slide proto oncogen and oncogen
12/4/2010
Proto Oncogen and Oncogen
• Oncogen
– Proteins that possess the ability to cause cellular
transformation.
– Act in a dominant fashion, either overexpression
or activating mutations.
Cellular transformation.
morphologic changes,loss of contact
inhibition,anchorage independent growth,ability
to form tumors when transplanted into nude
mice.
• Proto-oncogene.
– Potential to become activated into a cancer
causing oncogene.
– Have been found in all multicellular organisms.
– Would be involved : basic essential functions of
the cell related to control of cell proliferation and
differentiation.
– In normal cell : expression is tightly controlled.
1
12/4/2010
Proto-oncogenes
• 1.Growth Factors
– Stimulate cells in stationary stage to enter the cell
cycle.
– Occurs in a two stage process :
• Stimulation to proceed into G1 provided by
PDGF,EGF,followed by progression factors :IGF to
progress through the cell cycle.
– Action via autocrine and paracrine model.
2
12/4/2010
• 2.Growth factor receptors
– Link the information from extracellular
environment (GF) to a number of different
intracellular signaling pathways.
– The most important : transmembrane receptor
tyrosine kinases.
3
12/4/2010
• 3. Signal transducers.
– Cytoplasmic nonreceptor tyrosine kinases.
– Proteins with enzyme activity such as
phospholipase C , PI3-K
– Adaptor proteins : Grb2
– SH2 and SH3 domain.
– Three major pathways : PI3-kinase (PI3-K/AKT
pathway,RAS/mitogen-activated protein kinase
(MAPK) pathway,JAK/STAT pathway.
4
12/4/2010
• 4. Nuclear proto-oncogne and transcription
factors.
– Involved in the control of gene expression by their
action on DNA itself
– Final site of action for messages sent from GF.
– Level at which control of growth and proliferation.
5
12/4/2010
6
12/4/2010
Mechanisms of oncogene activation
• 1. Structural alteration.
– Point mutations
– Chromosomal translocation
– Truncated form of protein (transition mutation)
• 2. Amplification
• 3. Deregulated expression
– Insertional mutagenesis
– Translocation.
7
12/4/2010
8
12/4/2010
9
12/4/2010
Apoptosis
• Programmed cell death
• Intracellular machinery responsible for
apoptosis is called caspases.
• Caspases
• Synthesized in the cell as inactive precursor called
procaspases
• Usually activated by cleavage at aspartic acids by other
caspases.
10
12/4/2010
Tumor suppressor genes
• Play an important role in tumorigenesis.
• Involved in the control of abnormal cell
proliferation.
• Loss or inactivation : association with the
development of malignancy.
Tumorsuppressor genes
• The majority of p53 mutations (80%) in breast
cancer are missense, while 20%: nonsense
mutations, deletions, insertions
• P53 protein (21kD) normally inhibits Cdk (Cyclin
dependent kinase) enzymes.
• Recent evidence indicates that other damaged or
deleted Tumorsuppressor genes may code for
enzymes involved in DNA Repair mechanisms.
• If DNA repair mechanisms are incomplete, a
complex mechanism involving P53 leads to
programmed cell death or Apoptosis
11
12/4/2010
Carcinogenics
• Radiant energy
• Chemical compounds
• Viruses ( DNA virus,RNA virus, Adeno virus)
• These act by causing mutations or by introducing novel
genes into cells
• Familial conditions (Tumor suppressor genes)
• Oxidative damage to DNA increase the
mutations rate
12
12/4/2010
13
12/4/2010
14
12/4/2010
Tumor metastasis
• Metastasis is the most dangerous property of
tumor cells
• The cell grow as secondary tumors
• Many changes have been documented at the
surfaces of malignant cells
• Some are: alterations in transport property,
diminished adhesion, loss of certain antigens
etc
15
12/4/2010
The invasion-metastasis cascade
Tumor Initiation and Metastasis
Chiang A and Massague J. N Engl J Med 2008;359:2814-2823
16
12/4/2010
Patterns of Metastatic Spread of Solid Tmors
Patterns of metastatic
spread of solid tumor
Genes, Functions, and Cellular Players in Organ-Specific Metastasis
Genes,functions and cellualr players
in organ specific metastasis
17
12/4/2010
18
Proto Oncogen and Oncogen
• Oncogen
– Proteins that possess the ability to cause cellular
transformation.
– Act in a dominant fashion, either overexpression
or activating mutations.
Cellular transformation.
morphologic changes,loss of contact
inhibition,anchorage independent growth,ability
to form tumors when transplanted into nude
mice.
• Proto-oncogene.
– Potential to become activated into a cancer
causing oncogene.
– Have been found in all multicellular organisms.
– Would be involved : basic essential functions of
the cell related to control of cell proliferation and
differentiation.
– In normal cell : expression is tightly controlled.
1
12/4/2010
Proto-oncogenes
• 1.Growth Factors
– Stimulate cells in stationary stage to enter the cell
cycle.
– Occurs in a two stage process :
• Stimulation to proceed into G1 provided by
PDGF,EGF,followed by progression factors :IGF to
progress through the cell cycle.
– Action via autocrine and paracrine model.
2
12/4/2010
• 2.Growth factor receptors
– Link the information from extracellular
environment (GF) to a number of different
intracellular signaling pathways.
– The most important : transmembrane receptor
tyrosine kinases.
3
12/4/2010
• 3. Signal transducers.
– Cytoplasmic nonreceptor tyrosine kinases.
– Proteins with enzyme activity such as
phospholipase C , PI3-K
– Adaptor proteins : Grb2
– SH2 and SH3 domain.
– Three major pathways : PI3-kinase (PI3-K/AKT
pathway,RAS/mitogen-activated protein kinase
(MAPK) pathway,JAK/STAT pathway.
4
12/4/2010
• 4. Nuclear proto-oncogne and transcription
factors.
– Involved in the control of gene expression by their
action on DNA itself
– Final site of action for messages sent from GF.
– Level at which control of growth and proliferation.
5
12/4/2010
6
12/4/2010
Mechanisms of oncogene activation
• 1. Structural alteration.
– Point mutations
– Chromosomal translocation
– Truncated form of protein (transition mutation)
• 2. Amplification
• 3. Deregulated expression
– Insertional mutagenesis
– Translocation.
7
12/4/2010
8
12/4/2010
9
12/4/2010
Apoptosis
• Programmed cell death
• Intracellular machinery responsible for
apoptosis is called caspases.
• Caspases
• Synthesized in the cell as inactive precursor called
procaspases
• Usually activated by cleavage at aspartic acids by other
caspases.
10
12/4/2010
Tumor suppressor genes
• Play an important role in tumorigenesis.
• Involved in the control of abnormal cell
proliferation.
• Loss or inactivation : association with the
development of malignancy.
Tumorsuppressor genes
• The majority of p53 mutations (80%) in breast
cancer are missense, while 20%: nonsense
mutations, deletions, insertions
• P53 protein (21kD) normally inhibits Cdk (Cyclin
dependent kinase) enzymes.
• Recent evidence indicates that other damaged or
deleted Tumorsuppressor genes may code for
enzymes involved in DNA Repair mechanisms.
• If DNA repair mechanisms are incomplete, a
complex mechanism involving P53 leads to
programmed cell death or Apoptosis
11
12/4/2010
Carcinogenics
• Radiant energy
• Chemical compounds
• Viruses ( DNA virus,RNA virus, Adeno virus)
• These act by causing mutations or by introducing novel
genes into cells
• Familial conditions (Tumor suppressor genes)
• Oxidative damage to DNA increase the
mutations rate
12
12/4/2010
13
12/4/2010
14
12/4/2010
Tumor metastasis
• Metastasis is the most dangerous property of
tumor cells
• The cell grow as secondary tumors
• Many changes have been documented at the
surfaces of malignant cells
• Some are: alterations in transport property,
diminished adhesion, loss of certain antigens
etc
15
12/4/2010
The invasion-metastasis cascade
Tumor Initiation and Metastasis
Chiang A and Massague J. N Engl J Med 2008;359:2814-2823
16
12/4/2010
Patterns of Metastatic Spread of Solid Tmors
Patterns of metastatic
spread of solid tumor
Genes, Functions, and Cellular Players in Organ-Specific Metastasis
Genes,functions and cellualr players
in organ specific metastasis
17
12/4/2010
18