2. • Proto-oncogenes : Normal cellular genes whose products promote cell
proliferation
• Oncogenes : Mutated or over expressed versions of proto-oncogenes
that function autonomously having lost dependence on normal growth
promoting signals
• Onco-proteins : A protein encoded by an oncogene that drives increased
cell proliferation
4. • Proto oncogenes have multiple roles but all participate in signalling
pathways that drive proliferation.
• Proto oncogenes may encode growth factors, growth factor
receptors , signal transducers, transcription factors or cell cycle
components.
• Proto oncogenes oncogenes oncoproteins
(constitutively active)
mutation
5. GROWTH FACTORS
• Normal cells require stimulation by growth factors to proliferate.
• Most soluble growth factors paracrine
• However some cancer cells autocrine
• Examples : Glioblastoma (PDGF and PDGFR)
Many sarcomas ( TGF – α and EGFR)
6. • In tumors in which an autocrine loop is activated, the growth factor
gene is usually normal but
• The signals transduced by other oncoproteins cause overexpression
and increased secretion of growth factors.
• This causes initiation and amplification of the autocrine loop.
7. GROWTH FACTOR RECEPTORS
• A 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 and
A cytoplasmic tyrosine kinase domain
8.
9. • Receptor tyrosine kinases can be constitutively activated by many
mechanisms like
Point mutations
Gene rearrangements
Gene amplifications
10. • Point mutations – ERBB1 is a proto oncogene that encodes EGFR.
Point mutations in ERBB1 causes constitutive
activation of EGFR seen in a few Lung Adeno Ca.
• Gene amplifications – ERBB2 encodes HER2.
ERBB2 amplification is seen in certain breast
carcinomas leading to over expression of HER2
receptor and constitutive tyrosine kinase activity.
11. • Gene rearrangements : Activate other receptor tyrosine kinases.
• Eg : Deletion of a part of chromosome 5
Fusion of part of ALK gene with part of EML4 gene
Chimeric EML4 ALK protein
(constitutive tyrosine kinase activity)
12. SIGNAL TRANSDUCTION PROTEINS
• Receptor tyrosine kinase activation stimulates RAS and two major
downstream signalling arms
1. The MAPK cascade
2. PI3K/AKT pathway
• These pathways are frequently involved by the gain of function
mutations in different types of cancer.
13.
14. • RAS MUTATIONS - Point mutations in RAS family of genes constitute
the most common abnormality involving proto oncogenes.
• 15 – 20% of all human tumours express RAS mutation.
• RAS genes are of 3 types – HRAS,KRAS,NRAS
• RAS proteins are members of a family of membrane associated small
G proteins.
• Mutations markedly reduce the GTPase activity of RAS.
15.
16. • MUTATIONS IN BRAF : BRAF is a serine/threonine protein kinase.
• Activating mutations in BRAF stimulate the downstream kinases and
ultimately activate the transcription factors.
• These mutations are seen in 100% of Hairy cell leukaemias, >60% of
melanomas, 80% of benign nevi and to a smaller extent in a wide
variety of neoplasms.
17. • MUTATIONS IN PI3K FAMILY OF PROTEINS :
• PI3K is a heterodimer with regulatory and catalytic subunits and has
several tissue specific isoforms.
• It is recruited by activated receptor tyrosine kinase.
• It activates a cascade of serine/threonine kinases including AKT which
is a key signalling node.
• AKT has many substrates like mTOR,BAD,FOXO.
19. • PI3K is negatively regulated by an important braking factor PTEN.
• Alterations in virtually all components of the PI3K/AKT pathway have
been found in various cancers.
• PI3K(gain of function) and PTEN(loss of function) are the most
commonly mutated ones.
• PI3K mutations generally affect the catalytic subunit and result in
increased enzymatic activity.
20. • ALTERATIONS IN NON RECEPTOR TYROSINE KINASES :
• Mutations that confer oncogenic activity occur in several non
receptor tyrosine kinases also.
• They can be chromosomal translocations or rearrangements.
• They create fusion genes encoding constitutively active tyrosine
kinases.
• Eg : ABL tyrosine kinase
21. • Many different oncogenic tyrosine
kinases consist of fusion proteins in
which non tyrosine kinase partner
drives self association.
In this example BCR promotes self
association which is sufficient to
unleash the tyrosine kinase activity
of ABL.
22. • Oncogene addiction : The tumour cells are highly dependant on the
activity of one or more oncogenes.
• For example despite accumulation of mutations in other cancer
associated genes in CML cells, signalling through BCR – ABL tyrosine
kinase is required for most tumour cells to survive and proliferate.
• Hence inhibition of its activity is a highly effective therapy.
23. • Non receptor tyrosine kinases can also be activated by point
mutations that evade the negative regulatory check of the enzymes.
• Eg : JAK2 mutation
• Activating point mutations in JAK2 relieve the normal dependence of
hematopoietic progenitors on growth factors like erythropoietin.
• Disorders associated with JAK2 mutations are several
myeloproliferative disorders like polycythemia vera, essential
thrombocytosis and primary myelofibrosis.
24. TRANSCRIPTION FACTORS
• All the signal transduction pathways converge on the nucleus where
expression of the target genes advance the cell through mitotic cycle.
• The ultimate consequence of deregulated signalling pathways is
inappropriate and continuous stimulation of transcription factors.
• So , growth autonomy can also occur due to the mutations of
transcription factors that regulate the expression of pro growth genes
• Transcription factors of this class include the products of MYC, MYB,
JUN, FOS, REL proto oncogenes.
25. • MYC : It is present in virtually all eukaryotic cells.
• It belongs to immediate early response genes that are rapidly and
transiently induced by RAS/MAPK pathways.
• Several SNPs that are strongly linked to elevated risk of prostate and
ovarian cancers fall within a large region devoid of recognizable genes
adjacent to MYC on chromosome 8.
• These genetic variants alter the function of enhancer elements that
regulate the function of MYC expression
26. Chromosome 8
MYC
SNPS in this location are linked to elevated risks of
ovarian and prostate cancer
28. • MYC can be deregulated by a variety of mechanisms like
Genetic alterations of MYC
MYC translocations – Burkitt’s lymphoma and few B & T cell tumours
MYC amplifications – breast colon and lung cancers
Oncogenic mutations involving components of upstream signalling
pathways elevate MYC protein levels.
• Thus constitutive RAS/MAPK, NOTCH, WNT, HEDGEHOG signalling can
all transform cells in part through upregulation of MYC.
29. CELL CYCLE REGULATORS
• Orderly progression of the cells through cell cycle is regulated by
cyclins and cyclin dependant kinases(CDKs).
• The Cyclin-CDK complexes phosphorylate crucial target proteins that
drive cells forward through cell cycle.
• While cyclins activate CDKs, there are several CDK inhibitors that exert
a negative control over cell cycle.
30. • There are two main cell cycle checkpoints.
1. At G1/S transition and
2. G2/M transition.
• These are tightly regulated by a balance between growth promoting
and growth supressing factors as well as by sensors of DNA damage.
• When activated, these DNA damage sensors arrest cell cycle
progression and if cell damage cannot be repaired initiate apoptosis.
31. • Defects in G1/S checkpoint are more important in cancer as they lead
to dysregulated growth and mutator phenotype.
• Mutations that affect G1/S checkpoint can be broadly divided into
1. Gain of function mutations of cyclin D and CDK4 oncogenes that
promote G1/S progression.
2. Loss of function mutations in tumour suppressor genes that inhibit
G1/S progression.
32. TAKE HOME MESSAGE
• Proto-oncogenes may encode growth factors, growth factor
receptors, signal transducers, transcription factors, or cell cycle
components.
• The corresponding oncogenes generally encode oncoproteins that
serve functions similar to their normal counterparts, with the
important difference that they are usually constitutively active.
33. • GROWTH FACTORS :Glioblastomas, sarcomas
• GROWTH FACTOR RECEPTORS:
1)Point mutations – A subset of Lung Adenocarcinomas
2)Gene amplification – Breast carcinoma
3)Gene rearrangement – Lung cancer
• SIGNAL TRANSDUCTION PROTEINS:
1)RAS mutations - Pancreatic adenocarcinoma, cholangiocarcinoma
2)BRAF mutations – Hairy cell leukaemia, melanomas
3)PI3K mutations – Breast carcinoma
4)Non receptor tyrosine kinase – CML
34. • TRANSCRIPTION FACTORS:
1)MYC translocation – Burkitt’s lymphoma
2)MYC amplification – Breast colon and lung cancers
• CELL CYCLE REGULATORS:
1) Gain of function mutations in CyclinD and CDK4 – Lymphomas,
melanomas and sarcomas
2) Loss of function mutations in tumour suppressor genes – Pancreatic
carcinomas, Glioblastoma, ALL
