oncogenes Flashcards
how many genes are associated with germline mutations and somatic mutations?
70 germline and 342 somatic
what is a point mutation
the substitution of one base pair of a DNA sequence by another e.g. C-G is replaced by A-T
missense mutation
when there is a substitution which results in a different amino acid and a change in protein function
what happens if the point mutation is at a splice junction site
correct splicing doesnt happen and whole exon is missed out
translocation mutation
part of one chromosome is joined to another
how to detect translocation mutation
karyotypic (cytogenetic) analysis of tumour cells
what does gene amplification do to levels of mRNA transcribed from the gene
increases them, leading to increase in proteins
oncogene families (4)
growth factors, growth factor receptors, signal transduction proteins and nuclear regulatory proteins
type of growth factor receptors
Receptor tyrosine kinases
2 types of signal transduction proteins
protein tyrosine kinases and secondary signalling molecules
2 types of nuclear regulatory proteins
transcription factors and cell cycle proteins
what is RAS
small GTPase
what do the RAS genes encode
21-kDa guanine nucleotide binding proteins that locate at the surface of the cell membrane via lipid tail
what does RAS do
regulates length of time a signal is transduced from its upstream RTK
what is an RTK
receptor tyrosine kinase
what is a receptor tyrosine kinase
transmembrane receptor with cytoplasmic domains which act as tyrosine kinases when extracellular ligand is bound
when is the RAS protein activated
when a growth factor binds to its receptor
what happens when RAS is activated
it causes a cascade of intracellular phosphorylation which ends up activating a transcription factor, this makes CDKs and cyclins so the cell can go from G1-S phase
what happens when you have a mutated RAS gene
the RAS proteins on the cells membrane are already activated so the cascade of phosphorylation is always happening so there is an overproduction of CDKs and cyclins
what do MYC genes code for
proteins used for cell growth, survival and activity
what happens when the MYC gene is mutated
more cell growth, survival and activity. A cell can bypass the checkpoints in the cell cycle
what do oncogenes encode
oncoproteins - don’t need GFs to grow
how are the proteins encoded by ras genes activated
missense point mutations at 3 amino acids
how is Ras regulated
after p21 is formed a GTPase activating protein p120 associates with Ras-GTP, stimulating p21 GTPase activity
how does neurofibromin deactivate ras
it removes a phosphate
the problem of ras regulation in cancer
there are activating mutations at G12,G13 and Q61 which result in conformational changes to p21 so it does not interact with p120 as much. mutant ras then remains active
what does GAP mean
GTPase activating protein
what is required for ras-dependent transformation
functional Rho proteins
5 Ras directed therapies
- antisense oglionucleotides
- antisense RNA
- antisense ribozymes
- farnesyl transferase inhibitors
- immunisation against ras oncoproteins
what are antisense oglios/RNA/RNAi
small pieces of DNA/RNA which inhibit gene expression by acting on pre-mRNA or RNA targets
what are antisense oglios/RNA/RNAi advantages
ease of production, good heteroduplex formation
what are antisense oglios/RNA/RNAi disadvantages
rapidly degraded, delivery problems, large repeat doses needed
how are virus’ used against ras
they exploit ras pathways , activated ras allows for virus replication
farnesyl transferase inhibitors against ras
ras needs an attachment to the plasma membrane via a farnesyl group to the cystine of the carboxyterminal by farnesyl transferase
what happens if Kras or Nras is mutated
cancer is not responsive to ras targeted therapy
