Oncogenes Flashcards
What % of human genome can be translated
10%
What do genes consist of?
Protein-coding exons and non-coding introns
What are proto-oncogenes
Unmutated counterparts of oncogenes
How many proto-oncogenes are associated with:
- Germ line mutations
- Somatic mutations
Germ line: 70
Somatic: 342
What are the 2 basic classes of genes that lead to cancer?
Proto-oncogenes and tumour suppressor genes
What is different about germ line mutations? (as opposed to somatic)
Germ line mutations can be inherited from one generation to the next (eg APC and P53)
Which hallmarks of cancer are involved in oncogenes?
Genomic instability
Tumour promoting inflammation
What are the 10 hallmarks of cancer
- Self sufficiency in growth signals
- Insensitivity to antigrowth/ growth inhibitory signals
- Evasion of apoptosis
- Limitless replicative potential
- Sustained angiogenesis
- Ability to invade and metastasize
- Reprogramming energy metabolism
- Evasion of immune system
- Genomic instability
- Tumour promoting inflammation
What causes the change from proto-oncogene to oncogene?
Mutations of the proto-oncogene
What are the 4 types of mutations?
Point mutation
translocation
gene amplification
deletion
What is a point mutation?
Substitution of one base pair of a DNA sequence by another. May have effects depending on its position
What is a missense mutation?
Type of point mutation where one amino acid is substituted for another, resulting in identical protein to wild type apart from one AA change
What is a stop codon nonsense mutation?
Type of point mutation where mutated sequence encodes a signal for termination of translation (stop codon).
Results in truncated protein due to early termination
What happens if a point mutation occurs in splice junction site?
Correct splicing events may not take place, whole exon may be missed out of mRNA
What is a translocation mutation?
Part of one chromosome is joined to another, resulting in hybrid chromosome
How are translocation mutations detected?
Karyotypic analysis (chromosome mapping) of tumour cells detects translocated genes
What is gene amplification?
One copy of a gene multiplied thousands of times
How does gene amplification contribute to oncogenesis?
Increases levels of mRNA transcribed from genes, therefor increasing levels of protein encoded by amplified gene.
What is deletion?
Deletion of a single base pair.
What are the effects of a deletion mutation?
Can cause frame shift or accidentally code for a stop codon (truncated protein)
What is the difference between proteins and oncoproteins?
Oncoproteins do not require a growth factor, resulting in increased proliferation and malignant growth
What does protein does RAS encode and what is the protein involved in?
RAS encodes GTP-binding protein which is involved in growth signaling pathway.
What proteins can be oncogenes?
Growth factors (/ growth factor receptors)
Signal transduction proteins (eg protein tyrosine kinases)
Nuclear regulatory proteins (eg transcription factors, cell cycle proteins etc)
Describe how a normal cell would respond to a growth factor?
GFs activated by stimuli, and bind to GF receptors.
Activates RAS by converting GDP to GTP
Transmit signal to kinases which transmit signal to nucleus
Activate transcription factors which begin cell cycle
What are the 3 RAS genes?
H-ras, K-ras, N-ras
What type of mutation activates proteins encoded by genes of RAS family?
Missense point mutations
What do RAS genes encode?
21-kDa guanine nucleotide-binding proteins
AKA p21ras
What does RAS do?
Regulates length of time a signal is transducer from its upstream RTK
What is Sos? What is it involved with?
Sos is an exchange factor
It is involved with the conversion of GDP->GTP
What regulates RAS?
Cycle:
- formation of p21ras.GTP (active ras)
- Neurofibromin (GTPase activating protein) associates
- Stimulation of p21 GTPase activity, -> inactive ras
What happens if there is mutation in p21ras?
Reduce interaction, therefore GTP RAS cannot be converted back to GDP.
> cells continuously divide as increase activation of RAS pathway. (Cannot be inhibited)
What are rho and rac?
Cytoskeleton architectural proteins
What are antisense oligos?
Small pieces of DNA/RNA (~ 8-50bps) which inhibit gene expression by blocking transcription of molecules downstream
What are the pros and cons to using antisense oligos?
+ easy production
- rapidly degraded by endonucelases
- problems with delivery
- large repeat doses required
How is reovirus therapy used to kill cancer cells?
Virus exploits RAS pathway and only targets cancer cells.
