Oncogenes and Tumour Suppressor Genes Flashcards
What is the difference between proto and oncogenes?
3 egs?
Proto-oncogenes: normal genes which regulate cell growth and differentiation.
Oncogene: a proto-oncogene that has been activated by mutation or overexpression
HER2, KRAS, C-myc
3 types of alteration which forms oncogenes w clinical examples for each?
Point Mutation: variant in proto-oncogene (KRAS in lung + pancreatic cancer) or in promoter element
Gene Amplification: multiple gene copies (HER2 in breast cancer)
Chromosomal Translocation: creation of fusion protein (c-myc in Burkitt’s lymphoma) or disruption of regulatory elements
3 key characteristics of proto oncogenes when they develop mutations?
Proto-oncogene mutations to form oncogenes are often dominant
- however, despite this Proto-oncogene mutations are rarely inherited!
Therefore, a single oncogene copy is sufficient to promote tumorigenesis
What does HER2 gene code for? & what kind of activity does it have?
What is needed for HER2 activation and how can HER2 cause cancer?
HER2 codes for human epidermal growth factor receptor 2 + has intracellular tyrosine kinase activity
Growth factors bind EGFR or HER3 and alter receptor conformation–> activation
HER2 dimerisation downregulates p27 protein tumor suppressor -> cancer
HER2 is amplified in ~20% of invasive breast cancers! Poor prognosis :(
2 therapies are used to target HER2 associated cancers? & compare their mechanisms
Trastuzumab & pertuzumab= targeted monoclonal Ab.
Both downregulate/ block HER2 gene expression
Trastuzumab blocks ligand independent HER2-HER3 dimerisation
Pertuzumab binds to extracellular dimerisation domain of HER2 (stopping HER2 gene expression)
suele in combo w chemo
Function of KRAS/RAS/ What do their gene products do?
How to active RAS?
Explain RAS switch? + how mutation of this leads to cancer
Ras proteins = cellular signal transducers - therefore control transcription +regulate cell growth
Activated receptor tyrosine kinases activate Ras proteins
Normally Ras is tightly controlled via switch on/off
On= bound to GTP. Off= GTP break up to GDP
KRAS mutations: point mutations affecting hotspots at codons 12, 13 + also 18, 61, 117, 146 at lower Hz
- this leads to Mutated GTPase, which cant hydrolyse GTP -> irreversible Ras activation = permanent cell growth
Undruggable target!
What is c-myc? 3 things it is involved in
how is c-myc involved in Cancer?
c-myc: family of genes encoding for transcription factors
Involved in: proliferation, metabolic transformation, inc. metastatic capacity
Translocation between chromosome 8 (c-Myc proto-oncogene) & 14 (Ig heavy chain gene) = c-myc gene overactivation -> Burkitt’s lymphoma
Myc protein inhibitors + Myc protein destabilizing drugs = promising😍
What are tumour suppressor genes? + 4 ways they work?
3 egs of TSG’s?
Inhibit replication and proliferation of damaged cells by:
- Repair of DNA damage (e.g. MLH1, BRCA1/2)
- Apoptosis (TP53)
- Blocking proliferation
- Oncogene antagonists
BRCA1/BRCA2, TP53, RB1
what are most loss of function mutations?
What is Knudson’s two-hit hypothesis?
Most loss-of-function mutations in TSGs=recessive.
however, 1 normal allele is sufficient for cellular control - Therefore a 2nd hit” of normal allele causes Heritable cancers to develop (due to loss of heterozygosity)
What would happen if there is a mutation in one of the DNA repair genes? What kind of mutational load do they have?
Defects in DNA repair genes= genomic instability
This leads to an increase in oncogene activation + loss of TSGs
Inherited DNA repair gene defects have high mutational load -> tumours!
Compare BRCA vs PARP
BRCA1 and 2 are involved in repairing double stranded DNA breaks
however PARP: proteins which fix single stranded breaks
difference between normal cells & BRCA mutated cells?
4 egs of PARP inhibitors + how they work?
Normal cells repair via homologous recomb.
BRCA1/2 mutated don’t have homologous recombination so they can’t repair
Ola, Ruca, Nira, Talazo: Olaparib, Rucaparib, Niraparib, Talazoparib
PARP inhibitors Inhibit base excision repair in BRCA mutated cells - they therefore cause accumulation of single stranded breaks–> double stranded breaks—> cell death!
Function of p53 (note TP53=gene, p53=protein)
What is it regulated by?
What effect do some TP53 mutations have?
How many cancers contains TP53 mutations?
In DNA damage, p53 stops cell cycle or induces apoptosis!
TP53 is regulated by MDM2, which targets p53 for degradation in lysosomes. This stops excess p53 accumulation and activity.
Some TP53 mutations have dominant negative effect ie mutant p53 interferes w remaining normal p53 = adenoma
50% cancers contain missense mutations in TP53 hotspots
2 alterations=loss of function= cancer
How would we restore mutated p53?
Current advances suggest use of small molecules (mira-1 and prima-1) can restore wild type p53 function
Function of RB1 gene? + How is it inactivated?
Compare sporadic vs familial retinoblastoma
MAPK signalling -> CDK4 & CDK6 activation which phosphorylates RB
phosphorylated RB no longer represses E2F1
Activation of E2F1 target genes allows progression through S-phase
