Hallmarks of C

Question 1

What is C ?

Answer 1

Cancer is a group of diseases characterized by uncontrolled cell growth and ability to metastasise due to genetic and epigenetic mutations.

Question 2

What are some of the causes of Mutations?

Answer 2

Radiation 
• Therapeutic drugs 
• Chemicals 
• Infections 
• Inheritance and Age

Question 3

What are Mutated genes that causes c called?

Answer 3

Mutated genes that causes cancer are called proto-oncogenes/oncogenes

Question 4

What are Tumour suppressor genes?

Answer 4

Tumor suppressor genes codes for protein that inhibit tumor growth and formation

Question 5

What is a oncogene gene ?

Answer 5

An oncogene is a gene in which the mutation has caused a gain of function.

• These mutations are usually dominant (one mutated allele is sufficient for the effect). (Examples HER2, RAS, EGFR, BCR-ABL)

Question 6

What is Tumour suppressor gene ?

Answer 6

A tumour-suppressor is a gene in which the mutation has caused a loss of function.

• These mutations are usually recessive (both the alleles must be mutated to produce an effect).
• Tumor suppressors regulate cell growth and survival, normally inhibit cell growth mechanisms, promote apoptosis (I.e: P53,PTEN, RB, p16)

Question 7

From proto-oncogenes to Oncogenes

Answer 7

• An oncogene is a mutated proto-oncogene whose protein product is produced in higher quantities or whose altered product has increased activity and therefore act in a dominant manner.
• Potential proto-oncogenes: Growth factors, growth factor receptors, intracellular signalling molecules, transcription factors, cell cycle regulators

Question 8

Examples of Oncogenes ?

Answer 8

Growth factors (i.e PDGF, EGF) 

Growth Factors receptors (i.e. EGFR) 

Intracellular Signal Transducers (i.e. RAS, B-RAF, MAPK, ABL, FLT3) 

Transcription Factors (i.e. AP1, c-myc)

Question 9

MAP Kinaase Pathway

Answer 9

MAP kinase activation by mitogens leads to induction of Myc, and hence G1-Cdk complex

finally, activation of G1-Cdk promotes entry into cell cycle

Question 10

EGF

Answer 10

The signalling pathway of EGF (Epidermal Growth Factor) 

EGF and its family of receptors is an important paradigm of how a signal from an extracellular factor can be transduced through the cell, regulate gen expression and trigger cell proliferation.

Question 11

Stepwise activation of EGF signalling pathway

Answer 11

Binding of the growth factor to the receptor 

Receptor dimerization 

Autophosphorylation 

Activation of intracellular transducers (RAS) 

Activation of a cascade of serine/threonine kinases (Raf, MEK, MAPK) 

Regulation of transcription factors for gene expression

Question 12

Binding of the growth factor, receptor dimerization and auto-phosphorylation

Answer 12

When EGF binds to EGFR the receptor changes its shape. This change allows two receptors to come together and induce kinase activation. The receptor undergoes autophosphorylation.

Question 13

Activation of intracellular transducers

Answer 13

The phosphorylated receptor recruits GRB and SOS proteins to the membrane.

SOS activates RAS. Activation occurs by exchange of GDP with GTP.

Question 14

Activation of intracellular transducers (RAS)

Answer 14

SH2 domain of GRB2 interacts with the phosphorylated intracellular domain of EGFR and the SH3 domain of GRB2 interacts with SOS.

 SOS is a GEF (Guanidine nucleotide Exchange Factor) 

When GTP binds to RAS it cause a conformational change that results in RAS activation and binding to downstream signa transudcers

Question 15

Activation of cascade of serine threonine kinase (RAF)

Answer 15

Activated RAS activates signal transducer RAF

. RAF phosphorylates and activates MEK 

MEK phosphorylates and activates MAPK 

Activated MAPK enters the nucleus and phosphorylates and activates Transcription factors.

Question 16

Regulation of transcription factor expression

Answer 16

ERK1/2 is a MAPK that upon activation enters the nucleus and phosphorylates and activates Transcription factors AP1 and myc.

 AP1 is not a single protein but made up of two proteins, fos and jun. AP1 activates the expression of CCND1, which encodes for Cyclin D1, a critical rregulator of the cell cycle.

Myc is a protein that promotes proliferation by regulating the expression of targets genes, including NRas.

Question 17

Typically, Ras point mutations destroy its GTPase activity, leaving it permanently “on”

Answer 17

Mutations prevent GTP hydrolysis (i.e. enzyme activity destroyed)

Mutant Ras protein accumulates in a form in which it activates MAP kinase pathway

• Change active site
• Reduce GAP binding

Question 18

Ras, the “Rat sarcoma” oncogene

Answer 18

Monomeric GTP-binding protein (G protein)

• Activated by mitogen signalling

• Activates MAP kinases
• Mutated in 20%-25% of human cancers
• Mutated in 90% of pancreatic cancers
• Point mutations are common

Question 19

Typically, Ras point mutations destroy its GTPase activity, leaving it permanently “on”

Answer 19

Mutations prevent GTP hydrolysis (i.e. enzyme activity destroyed)

Mutant Ras protein accumulates in a form in which it activates MAP kinase pathway

• Change active site • Reduce GAP binding

Question 20

Activation of several oncogenes accelerates tumour development

Answer 20

Activated Myc and Ras genes introduced into mouse genome (“transgenic mice”) alone or together

Question 21

BCR-ABL Fusion

Answer 21

ABL cytoplasmic and nuclear protein tyrosine kinase. Abl plays a role in DNA repair,

Cell division, differentiation, adhesion and stress response

• BCR is an Activation of GTP-binding proteins
• BCR-ABL is a constitutive active Tyrosin kinase