Oncogenes Flashcards
What are the hallmarks of cancer?
independence in growth signals don't respond to anti-apoptotic signals limitless replication sustained angiogenesis altered metabolism evasion of immune system inflammation genomic instability ability to evade and metastasis
How do proto-oncogenes turn to oncogenes?
Through point mutations, translocations, deletion, gene amplification
What are the types of point mutations?
missense
nonsense
frameshift
How can translocation change gene function and regulation?
It can be translocated near an overactive promoter resulting in overexpression of the gene
What are the configuration gene amplification causes?
- Double minute-tiny extrachromosomal bodies that segrate randomly during mitosis
- Homogeneously staining regions-expanded regions on the chromosomes without normal banding patterns
How does gene amplification contribute to oncogenesis?
By transcribing a large amount of MRNA
If deletions occur in multiples of 3’s then no frameshift will occur
True
What proteins can be oncogenes?
Trnascription factors, tyrosine kinase receptors or proteins, growth factors, secondary molecules
What are some examples of growth factors that can act as oncogenes?
FGF, PDGF, TGF-A(breast cancer viaEFGR)
How is the growth receptor activated?
Ligand binds receptors dimerize, conformational change and it oligomerizes, the intracellular domain is transphosphorylated by kinase activity and recruits secondary molecules and this initiates a signalling cascade
How can receptor growth factor contribute to cancer? Give exmaples
They can be overexpressed suh as c-erb(valine to glutamine causes neuroblastoma)
Or can be mutated such as v-erb both lead to constitutive activation
Steroid receptor, outline main steps. Give example of a mutation that occurs in steroid receptor and causes cancer
They are bound to a receptor and heat shock proteins when a ligand binds it will dissociate from the hsp complex and tranlocates to the nucleas binds to HRE and transcribes genes.
ABL;PAR translocation form a fusion protein one binds to DNA the other has transactivating function- Leukaemia
How are protein kinases mutated, give examples
Src-mutated then can lose cell cell adhesion-metastasis and can deregulate cell cycle
, c-abl- translocation of of abl from chromosome 9 to chromosome22, abl is constitutively expressed because of the strong promoter it is next to, found in CML
What is src what is important for?
SRCis a kinase that phosphorylates intracellular domian of kinase receptor, it’s on the plasma membrane. Important for cell-cell adhesion and cell cycle regulation via sam68
What drug can be used to treat bcr-abl philadiphea chromosome? And what are some problems with it?
sti-571 inhibitor against the signalling of bcr-abl
It is non specific, mutation arise and express AGP making it resistant to the drug later on.
What is myc and how does it work? What regulates it?
myc is a transcription factor that binds to max and translocates to nucleas to bind to e-box element on DNA
Important in regulating the cell cycle, apoptosis,metabolism, cell adhesion, differentiation. It inhibits p27 and activates cyclin-cdk complexes
Other myc families, APC regulates it through the wnt pathway
WHat is c-jun and how does it work?
Fos binds to jun after it gets proliferative and differentiation signalling, then it binds to AP1 sites
What is ras? How is the MAPK activated?
a 21kda guanine nucleotid ebinding protein(p21ras)
Ligand binds, ras is phosphorylated by GAP(P120), it oactivates raf, which activates MAPKKK, which activates MAPKK and then MAPK which goes to the nucleus and trasncribe genes. Gtpase turns ras off and the signalling cascade is all turned off.
Which codons have ras muations? What are the different RAS genes?
12,13,61
N,H,K
What is NF1
It is a tumour suppresson gene, homologous to ras
What are ways to target ras?
antisense oligos or RNA
farensyl transferase inhibitor
RNAi
