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.
 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.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. 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. 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.
 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.
 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.
 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
 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
 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.
The invasion-metastasis cascade
 Tumor Initiation and Metastasis

Chiang A and Massague J. N Engl J Med 2008;359:2814-2823

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