this covers the mechanism of signals and receptors in preservation of cancer.

1. Self-Sufficiency in Growth
Signals
TSMU
Siddhant Kushare
Group 1 Semester 5

2. What is Proto-Oncogene and Oncogene
• Proto-oncogenes are normal cellular gene which causes cell growth
and proliferation, After required growth is achieved, proto-oncogenes
are switched off and then we can say that Normal Activity of proto-
oncogenes are regulated (Controlled).
• Oncogenes are mutated version of Proto-Oncogene or Overexpressed
version, They are encoded and promotes excessive growth and
proliferation in absence of any growth promoting signals. Activity of
oncogenes cannot be regulated ( Not Controlled).

3. How Does Normal Cell Responds To Growth
Factor. • Aberration can occur at any point:
1. Growth Factor
2. Growth Factor Receptor
3. Protein Involved In Signal
Transduction
4. Nuclear Regulatory Protein
(Transcription Factor)
5. Proteins Involved In Cell Cycle
Regulation( Cyclins , Cyclin
Dependent Kinase)

4. Growth Factor
• A growth factor is a naturally occurring
substance capable of stimulating cell
proliferation, wound healing and
occasionally cellular differentiation.
• Usually it is secreted Protein or a steroid
hormone.
• Most soluble growth factor are made by
one cell type and act on neighbouring
cell to stimulate proliferation (paracrine
action)

6. Growth Factor Receptor
• From Large No. of Oncogenes encoded
Growth Factor Receptor, Receptor
Tyrosine Kinase (RTK) are most
important.
• There is auto phosphorylation of tyrosine
residues in its own tail -> RAS
• But in Cancer , These GFR[R.T.K] are
mutated, leading to constitutive GF
independent Tyrosine Kinase activity.
• RTK are constitutively activated in tumor
a by multiple mechanisms including
Pt.mutations, Gene Re-arrangements and
Gene amplification.

8. Proteins Involved In Signal Transduction
• Cancer cells often acquire growth autonomy as a result of mutations
in genes that encode components of signaling pathways downstream
of growth factor receptors.
• There are 2 important oncoprotiens in category of signaling molecules
are RAS and ABL .
• RAS is most commonly mutated and Important signal transduction
protein.

9. RAS Protein
• RAS is a member of a family of small G proteins that bind
GTP and GDP.
• Activated RAS stimulates downstream regulators of
proliferation by several interconnected pathways that
converge on the nucleus and alter the expression of gene
that regulate growth, such as MYC.
• RAS most commonly is activated by point mutations in
amino acid residues that are either within the GTP-
binding pocket or in enzymatic region that carries out GTP
hydrolysis.
• Gain of function mutation in RAS cause uncontrollable
activity And Loss of function mutations in GAP also cause
uncontrollable RAS activity.

10. Mutation in MAP-K and P13K/AKT Cascade
• Both MAP-K and P13K/AKT lie downstream to RAS.
I. Mutation in BRAF
It is a member of RAF Family
Serine / Threonine protein kinases.
Present in 100% hairy cell leukaemia
>60 %Melanomas
Langerhan cell histiocytosis
Colon Cancer
BRAF Activation mutation will stimulate MAP-K pathway which will increase
downstream growth pathway.

11. I. Mutation in kinases of P13K family
Very common in certain Cancers
RTK —>ATK (major signaling node) —>mTOR —>Protein and lipid
synthesis .
P13K is regulated by a breaking Factor called PTEN which converts
P13K to ATK ( due to which there is decrease signal transduction)
Gain of function mutation in P13K causes 30% breast Cancer.
PTEN —> Tumor suppressor gene ( decreases signaling
transduction). Loss of function mutation causes Cancer.
• Oncogene Addiction:
Phenomenon where some tumors are dependent on single oncogenic
protein for sustained Growth and proliferation.
Inhibition of this specific oncogene is sufficient to halt the neoplastic
phenotype.

12. Non-Receptor Tyrosine Kinase
• They can have 2 forms of mutations
1. Mutation in form of chromosomes translocation or
re-arrangements:
- They create Fusion genes
-encode constitutively active tyrosine kinase.
In chronic myelogenous leukaemia (CML) and some
ALL,ABL gene is translocated from its normal location
on chromosome 9 to chromosome 22 where it fuse at
the BCR gene to form ABL-BCR hybrid gene which
activates growth signalling pathways.

13. • BCR-ABL Hybrid Gene are Chimeric Gene.
• BCR-Moiety promotes self association of BCR-ABL which is sufficient
to unlease the tyrosine kinase activity of ABL.
• Treatment for CML is to give BCR-ABL kinase inhibitors.
• Rare CML stem cells persist, which harbour BCR-ABL Fusion gene,
apparently because these cells do not require BCR-ABL signals for
their survival. That’s why treatment is life long .
1) N.R.T.K are also affected by point mutations:
N.R.T.K normally have negative auto-regulatory function that keeps
enzyme activity in check.
One ex. JAK-2 so point mutation in JAK-2 due to which there will be
constitutive JAK/STAT signalling pathway. Due to which tumor is
relieved from normal dependence on growth factor.

15. Nuclear Regulatory Protein
• All signal transduction pathways converge onto the
nucleus.
• This proteins stimulate the transcription factors and
Enter cell cycle resulting in growth and proliferation.
• Normally there is a transient activation of
transcription factors but mutations in transcription
factor will lead to uncontrolled cell cycle causing
growth and proliferation.
• Transcription Factors includes: MYC,MYB , JUN , FOS ,
REL

16. • The most common TF encoded protooncogene tonne mutated in cancer is
MYC.
MYC- Oncogene :
Normally they are rapidly and transiently induced by RAS / MAP-K signalling.
MYC activate expression of many genes that are involved in cell growth:
A. MYC targets genes like D-Cyclins which are directly involved in cell cycle
progression.
B. MYC unregulates expression of rRNA and increase rRNA processing
resulting in increased protein synthesis.
C. MYC is also involved in Metabolic Reprogramming(Warburg- effect)which
is one of the hallmark of cancer . MYC will stimulate multiple glycolytic
enzymes and Factors involved in Gultaming Metabolism which leads to
synthesis of macromolecules like DNA, Protiens and Lipids which are the
requirements of cancer cells.

17. • MYC is the master transcription regulator for cell growth ex.
Burkett lymphoma .
• MYC increases expression of telomerase.
• MYC is capable of converting somatic cells to stem cells —>
cancer cells.
• Mutations involving MYC are:
1. Translocations which involves MYC oncogene which
places MYC under control of enhancer’s causing increased
MYC expression. Examples are Burkett lymphoma and few
B&T cell tumors.
2. Amplification of MYC oncogene such as in Breast , colon ,
lung cancers. Some other examples are N-MYC(
neuroblastoma) and L-MYC ( small cell carcinoma of the
lung)
3. Increased upstream signaling pathway: such as
RAS/MAP-K signaling pathways, Notch signaling, WNT
signaling, Hedge Hog signaling pathway this all pathways
are up regulator of MYC

18. Cyclins and Cyclin-Dependent Kinases
• Growth factors transduce signals that stimulate the orderly progression of
cells through the various phases of cell cycle, the process by which cells
replicate their DNA in preparation for cell division. This cell cycle is
orchestrated by Cyclin-dependent kinases which are activated by binding to
Cyclins.
• CDK-cyclin complex phosphorylate crucial target protiens that drive cells
forward through the cell cycle. CDK inhibitors silence CDKs and exert negative
control over the cell cycle, Expression of these inhibitors is down regulated by
mitogenic signaling pathway causing progression of cell cycle.

19. • Cell Cycle Checkpoints :
G1/S : Checks the DNA integrity before allowing
DNA replication.
G2/M : Ensures there has been accurate DNA
replication by the cell actually divides.
• Cell cycle is regulated by activators and
inhibitors:
1. Cyclins : they are protiens synthesised
sequentially during cell cycle(D-E-A-B) , they
activate CDK by oxidative phosphorylation.
They bind to form Cyclin-dependent complex.
2. CDK : this are constitutively inactive and are
activated by relevant cyclins . Ex. CDK 4,6,2,1.
CDK-4/ Cyclin D , CDK-6/Cyclin D , CDK-
2/Cyclin E/A , CDK-1/Cyclin A/B.

20. • Inhibitors:
Cyclin Dependent Kinase Inhibitors (CDK-I) enforcers cell cycle
checkpoints by inhibiting cyclin-CDK complex .
There are total 2 families