Sustaining proliferative signals (oncogenes) Lecture 7 Flashcards
Define proto-oncogene and oncogene
Proto-oncogene - promotes normal cell growth and proliferation in a regulated manner
Oncogene = mutated forms of the correpotentially cancer causing gene, novel/unregulated functions, High level of expression
How can oncogenes be amplified to cause cancer?
Gain function mutations - only one allele needs to be mutated
Point mutation -> encoded protein with altered characteristics
Amplification of genomic DNA segment including proto-oncogene which leads to overexpression
Chromosomal Translocation that brings a growth regulatory gene under control of a different promoter giving inappropriate gene and protein expression
Chromosomal Translocation that joins two genes together -> creates a chimeric fusion gene and protein with novel characteristics e.g. BCR and ABL
Chromosomal translocation eg. 8:14/2/22 in Burkitts lymphoma The c-myc gene is placed near the immunoglobulin genes which are highly expressed in B cells and the expression of the c-myc gene is then constitutively increased Gene replication Double minute chromosomes
Key concept of oncogens
2 normal alleles produces normal protein
1 normal and 1 mutated allele produces half normal and half mutant protein
DNA amplification produces too much of normal protein
Describe Ras
Molecular switch
Can be present in active (GTP bound) or inactive (GDP bound) form
In mutated RAS it gets blocked in active form by blocking of intrinsic GTPase activity
Commonest oncogene mutated in human tumours
Common cancer causeing mutations at codons 12,13 or 61
What is MYC?
MYC is a Transcription Factor
- Usually binds E-box element located within promoters of target genes to upregulate them
- Works with MAX to recruit additional co-activators to the promoter of the target gene
- MAX also works with MAD1 to repress gene expression
- MYC proteins compete with MAD1 for binding to MAX
A MYCN amplification - takes two forms in causing neuroblastoma:
- Double minutes - chromatin structures without centromeres/telomeres
- Homogeneously staining region - hundreds of copies of MYC inserted into another chromosome
Within chromosome translocation that brings a grwoth regulatory gene under the control of a different promotor, descirbe the action of MTC and IGH giving inappropraite gene expression
- MYC gene is divided into its promoter regions
- In the translocation you get breakpoints where the coding region is separated from the regulatory segment
- On IGH there is a constant region and enhancer sequences
- Consequence of translocation is that coding region of MYC is brought under enhancer sequence of IGH gene - meaning MYC expression is driven instead of Ig gene
Within chromosome translocation that joins 2 genes together, What are PML and RARalpha and how can they cause cancer?
RARalpha is a nuclear receptor which functions as a Transcription Factor (upon ligand binding) for myeloid differentiation genes. Without ligand binding it represses genes
PML has an important role in cell survival / cycle regulation
When they fuse they homodimerise - enhancing transcriptional repression and silencing of genes important for myeloid differentiation. Also causes self renewal of APL (the most rapidly fatal leukaemia) cells
This causes Acute Myelocytic Leukaemia
How can APL be treated
Retinoic acid - converts PML/RARalpha from a transcriptional repressor to activator. This causes reactivation of genes so myeloid diffrentation is increased
Arsenic trioxide - PML/RARalpha degradation - brings back normal structured nucelar bodies which regulate p53
What is the importance of tyrosine kinase in cancer?
Amino acid changes or over expression can lead to contituative activation or constant phosphorylation and cell growth cascades Eg. Pp60c-src a non-receptor tyrosine kinase- often over expressed in colon, liver, lung, breast and pancreas tumours binds to phosphorylkated receptors and the kinase domain becomes active leading to survival and proliferation
How are tyrosine kinase inhibitors work and devlpoed in gernarations
How they work
- EGFR (epidermal growth factor receptor) has extracellular domain where EGF binds
- Intracellular domain, where kinase is, where ATP binds
- TKI mimics ATP and can bind to the ATP binding site causing the kinase to not be able to function
Development
First:
- Competitive ATP-mimics e.g gefitinib
- Reversible binding
- Frequent drug resistance
Second:
- Irreversible binding e.g. afatinib
- Toxicity is a problem
Third:
- Bind more avidly to EGFR mutants than wild-type EGFR
- Less toxicity
