Hallmarks of C Flashcards
What is C ?
Cancer is a group of diseases characterized by uncontrolled cell growth and ability to metastasise due to genetic and epigenetic mutations.
What are some of the causes of Mutations?
Radiation • Therapeutic drugs • Chemicals • Infections • Inheritance and Age
What are Mutated genes that causes c called?
Mutated genes that causes cancer are called proto-oncogenes/oncogenes
What are Tumour suppressor genes?
Tumor suppressor genes codes for protein that inhibit tumor growth and formation
What is a oncogene gene ?
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)
What is Tumour suppressor gene ?
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)
From proto-oncogenes to Oncogenes
- 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
Examples of Oncogenes ?
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)
MAP Kinaase Pathway
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
EGF
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.
Stepwise activation of EGF signalling pathway
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
Binding of the growth factor, receptor dimerization and auto-phosphorylation
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.
Activation of intracellular transducers
The phosphorylated receptor recruits GRB and SOS proteins to the membrane.
SOS activates RAS. Activation occurs by exchange of GDP with GTP.
Activation of intracellular transducers (RAS)
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
Activation of cascade of serine threonine kinase (RAF)
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.
Regulation of transcription factor expression
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.
Typically, Ras point mutations destroy its GTPase activity, leaving it permanently “on”
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
Ras, the “Rat sarcoma” oncogene
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
Typically, Ras point mutations destroy its GTPase activity, leaving it permanently “on”
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
Activation of several oncogenes accelerates tumour development
Activated Myc and Ras genes introduced into mouse genome (“transgenic mice”) alone or together
BCR-ABL Fusion
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
