Lecture 27 Flashcards
Are all genetic changes which occur in cancer random?
No there are some non-random changes reflecting specific gene alterations
What can cause gene amplification in cancer?
Extra chromosomes in which the gene is found Multiple small (double minute) chromosomes which contain the relevant gene Multiple copies of the gene arranged in a head to tail fashion in a chromosome
How does gene amplification affect cancer with regards to EGFR?
This gene is often amplified in cancer, this protein binds EGF and TGFalpha resulting in tyrosine kinase activity which induces cell growth
How does gene activation by deletion affect EGFR in cancer?
The ligand binding domain of the protein is lost, this results in loss of ligand regulation for the tyrosine kinase activity driving uncontrollable growth
What is the role of chromosome translocation in cancer?
Many characteristic transloactions are seen in cancer which results in the misregulation of genes as they are placed in new environments
How does chromosome transloaction play a role in Mantle cell lymphomas?
A t(11;14) mutation occurs where a section of c11 which contains BCL-1 is combined with a section on c14 resulting in BCL-1 being regulated by the IgH gene
How does point mutation lead to cancer?
Some genes such as RAS reqire only a single mutation to cause disease
Where can the oncogenic mutations occur in RAS?
1 of 3 locations:
codon 12.13 or 61
What is the difference between a partially transformed cell and a fully transformed cell?
A partially transformed cell has been immortalized while a fully transformed cell has undergone further oncogenic mutations which reduce dependance on growth factors,
reduce density-dependent inhibition of proliferation causing cells to form multiple layers,
Reduced adherence to substrate,
anchorage independant proliferation,
tumour formation in mice
What is an example of genetic inactivation inducing a cancer?
Retinoblastoma which is a rare cancer of the eye in children, caused by los of a normal RB1 gene
What is the pathogenesis of retinoblastoma?
The RB1 allele is lost on both chromosomes (one of these may be due to an inherited mutation)
inherited retinoblastoma develops in a single hit pattern as only one functional RB1 gene is inherited
Sporadic retinoblastoma requires two hits as both copies of the RB1 gene must undergo a mutation
What is an example of genetic inactivation via promoter methylation causing cancer?
Some cancers will have a functional RB1 gene but as the promoter is methylated they will not express its product as cytosines in the promoter are methylated resulting in the binding of repressors
What is the normal function of proto-oncogenes?
Activate proliferation
Suppress differentiation
What is the normal function of tumour suppressor genes?
Inhibit proliferation
Promote differentiation
What is the mechanism for oncogenic change in proto-oncogenes?
Amplification
Or deregulated activity (EGFR domain deletion)
Translocation (cyclin D)
Point mutation (Ras)
What are the changes to protein functions in proto-oncogenes that typically induce cancer?
Mutation gives increased or altered activity, typically gain of function
What changes to cell behaviours are induced by proto-oncogenes in cancer?
Drives abnormal cell growth
What is the mechanism for oncogenic change in tumour suppressor genes?
Gene silencing by methylation (RB1)
What are the changes to protein functions in tumour suppressor genes that typically induce cancer?
Mutation gives less activity or loss of function
What changes to cell behaviours are induced by tumour suppressor genes in cancer?
Releases cells to an abnormal phenotype
What are the 4 stages of the cell cycle?
Mitosis, Gap1 (G1), S (DNA Synthetic Phase), G2
What occurs in mitosis?
Culmination in cytokiensis where two daughter cells are produced
What occurs in G1 phase?
Cells sense the environment for growth factors, space and substrate attachment to determine if they should enter cell division or not
If non-proliferating state is enetered then the cell remains in a G0 phase
What is the restriction point?
The point in the G1 phase where the cell decides if it will enter another round of cell division or not control of this point is lost in cancer
What occurs in the S phase?
DNA is replicated in preparation for cell division
These cells can be recognised by providing marked DNA precursors
What occurs in the G2 phase?
Quality control pathways check the competion of replication, and cells prepare for mitosis
How is control over the cell cycle regulated?
Cyclin dependant kinases which contain both catalytic and regulatory units
These proteins oscillate in concentration reaching peaks at
G1/S tansition, S phase, G2/Mitosis transition
What are the different cyclin-dependant kinases and when do they reach there peaks?
G1/S- Cyclin E-Cdk2
During S phase- cyclin A-Cdk2
G2/M- cyclin B-Cdk1
What is the role of growth factors with regards to the cell cycle?
Promotion of cell division (mitogenic compounds), this action is down via receptor dimerisation, TK activation, receptor phosphorylation and phosphorylation of signalling molecules
What may cause the EGFR to show excessive tyrosine kinase activity in cancer?
High concenctrations of growth factors
High concentrations of receptors
Mutant receptors lacking the ligand-binding domain
mutant receptor with signal base changes in the TK domain
What is the relationship between RAS proteins and Growth Factor Receptors?
These integrate signals from GF receptors, receptor activation causes RAS to bind GTP inducing a conformational change so that other signalling molecules can cause progression through the cell cycle
This stops when RAS hydrolyses GTP, in cancer this function is impaired
What is the function of the BCL-1 gene?
Activated via RAS signalling, encoding cyclin D1 which results in the activation of Cyclin-dependent kinase Cdk4 stimualting entry int othe cell cycle
I cancer regulation of this process and therefore entry into the cell cycle is lost
What is the function of the RB gene product?
pRb protein (from RB1 gene) exists in two forms which change within the cell cycle In early G1 it is weakly phosphorylated preventing entry into the cycle In late G1 it is heavily phosphorylated (ppRb) allowing entry into the cycle
What is the kinase that phosphorylates pRb and thus stimulates entry into the cell cycle?
Cyclin D (Cdk4) this phosphorylation eventually allows for the transcription of genes needed for the S phase of the cell cycle including cyclin E
