Proto-oncogenes and oncogenes

Melat Debebe
MD, Pathologist
• Proto-oncogenes: healthy gene found in the cell
- normal cellular genes whose products promote cell
proliferation
• Oncogenes: mutated or overexpressed versions of proto-
oncogenes that function autonomously, having lost
dependence on normal growth promoting signals
• Oncoprotein: a protein encoded by an oncogene that drives
increased cell proliferation through one of several
mechanisms
• Proto-oncogenes have multiple roles
- encode growth factors, growth factor
receptors, signal transducers, transcription
factors or cell cycle components
Growth Factors
• Normal cells require stimulation by growth
factors to proliferate
• Most growth factors are made by one cell type
and act on a neighboring cell to stimulate
proliferation (paracrine action)
• Some cancer cells, however, acquire the ability
to synthesize the same growth factors to
which they are responsive, creating an
autocrine loop
– Glioblastoma-PDGF and PDGFR
• In tumors where autocrine loop is activated,
the growth factor gene is usually normal
– Signals transduced by other oncoproteins cause
overexpression and increased secretion of growth
factors
– Thus causing initiation and amplification of the
autocrine loop
Growth factor Receptors
• Large number of oncogenes encode growth
factor receptors of which receptor tyrosine
kinase is one of the most important one
• They are transmembrane proteins with an
– Extracellular ligand binding domain
– A cytoplasmic tyrosine kinase domain
Receptor tyrosine kinases can be constitutively
activated by many mechanism like
• Point mutations
• Gene rearrangements
• Gene amplifications
• Point mutations
– ERBB1 is a proto-oncogene that encodes EGFR
– Point mutations in this gene causes constitutive
activation of EGFR seen in Lung Adenocarinoma
• Point mutation: is a genetic mutation where a
single nucleotide base is changed, inserted or
deleted from a DNA or RNA sequence
• Gene amplifications
– ERBB2 encodes HER2
– Seen in breast carcinomas leading to over
expression of HER2 receptor and constitutive
tyrosine kinase activity
• Gene rearrangements
– Activate other receptor tyrosine kinases
Signal transduction proteins
• Tyrosine kinase activation stimulates RAS and
two major downstream signaling arms
– The MAPK cascade
– PI3K/AKT pathway
– Which are frequently involved by the gain of
function mutations in different types of caner
RAS MUTATION: point mutations in RAS family of
genes constitute the most common abnormality
involving proto-oncogenes
- 15-20% of all human tumors express RAS
mutation
– RAS proteins are members of a family of membrane
associated small G proteins that binds GDP and GTP
– Mutations markedly reduce the GTPase activity of RAS
• Mutations in BRAF: BRAF is a serine/threonine
protein kinase that sits at the top of a cascade
of other serine/threonine kinases of the MAPK
family.
– Simulates the downstream kinases and ultimately
activate the transcription factors
– Are seen in hairy cell leukemia, melanoma, benign
nevi
Mutations of the PI3K family of proteins
• PI3K is a heterodimer comprised of regulatory
subunit and a catalytic subunit
• Recruited by activated receptor tyrosine
kinase
• Activates a cascade of serine/threonine
kinases including AKT
– Leading to increased enzymatic activity
• PI3K is negatively regulated by an important
braking factor PTEN
• PI3K(gain of function) and PTEN(Loss of
function) are the most commonly mutated
ones
Alterations in non receptor tyrosine kinases
• Can be chromosomal translocations or
rearrangements
• Create fusion genes encoding constitutively
active tyrosine kinases
• Despite their non-membranous localization,
most of these oncoproteins also activate the
same signaling pathways as receptor tyrosine
kinases.
• Oncogenic addiction: tumor cells are highly
dependent on the activity of one or more
oncogenes
• Despite accumulation of mutations in other
cancer associated genes in CML cells, signaling
through BCR-ABL tyrosine kinase is required
for most tumor cells to survive and proliferate
• Non receptor tyrosine kinases can also be
activated by point mutations that evade the
negative regulatory check of the enzymes
– Activating point mutations in JAK2 relieve the
normal dependence of hematopoietic progenitors
on growth factors
– Myeloproliferative disorders like polycythemia
vera, essential thrombocytosis and primary
myelofibrosis
Transcription factors
• All signal transduction pathway converge on
the nucleus where expression of the target
genes advance the cell through mitotic cycle
• The ultimate consequence of deregulated
signaling pathways is inappropriate and
continuous stimulation of transciption factors
• Growth autonomy- can also occur due to
mutations in transcription factors
• MYC: present in virtually all eukaryotic cells
– Belongs to immediate early response genes that
are rapidly and transiently induced by RAS/MAPK
pathways following growth factor stimulation of
cells
• MYC amplification: breast, colon and lung
cancer
• MYC translocation: Burkitt lymphoma
Cell cycle regulators
• Orderly progression of the cells through cell
cycle is regulated by cyclins and cyclin
dependant kinases
• Cyclin-CDK complexes phosphorylate crucial
target proteins that drive cells forward
through cell cycle
There are two main cell cycle checkpoints
• At G1/S transition
• At the G2/M transition
- Both regulated by a balance of growth
promoting and growth suppressing factors
- When activated, these DNA damage sensors
arrest cell cycle progression and if cell damage
cannot be repaired initiate apoptosis.
• Defects in G1/S checkpoint are more
important in cancer as they lead to
dysregulated growth and mutator phenotype
• Such mutation that affect G1/S checkpoint can
be broadly divided into
– Gain of function mutations of cyclin D and CDK4
oncogenes that promote G1/S progression
– Loss of function mutations in tumor suppressor
genes that inhibit G1/S progression
In a nutshell
• Proto-oncogenes may encode growth factors,
growth factor receptors, signal transducers,
transcription factors, or cell cycle components
• Corresponding oncogenes generally encode
onco-proteins that serve functions similar to
their normal counterparts, important
difference being that they are constitutively
active