genetics of cancer Flashcards
oncogenes and proto-oncogenes: define proto-oncogene and oncogene, explain the relationship between proto-oncogenes and oncogenes, recall how oncogenes disrupt cellular pathways and explain, with examples, how mutation of a proto-oncogene can disrupt normal cell division
6 hallmarks of cancer
sustaining proliferative signalling, evading growth suppressors, activating invasion and metastasis, enabling replicative immortality, inducing angiogenesis, resisting cell death
2 emerging hallmarks of cancer
deregulate cellular energetics, avoid immune destruction
2 enabling characteristics of cancer
genome instability and mutation, tumour-promoting inflammation
cell cycle: cycle checkpoints
G1/S (assess DNA damage), G2/M (assess duplicated DNA damage)
cell cycle: what can permanent activation of a cyclin lead to
driving a cell through a checkpoint
what do proto-oncogenes code for
essential proteins involved in maintenance of cell growth, division and differentiation
effect of mutation (e.g. single point mutation) on proto-oncogene
converts it into an oncogene, whose protein product no longer responds to control influences
3 ways oncogenes have expression or activity
aberrant expression, over-expression, aberrant activity
examples of how oncogenes can gain aberrant activity
if mutation in coding sequence in proto-oncogene, can change binding domain of inhibitory protein so can’t bind, or affect phosphorylation sequence so becomes constitutively active and can’t be switched off, creating an aberrantly active protein
example of how oncogenes can be over-expressed
if mutation in coding sequence in proto-oncogene which then undergoes gene amplification
how can oncogenes have aberrant expression
chromosomal translocation where promoter put in front of gene which isn’t usually expressed (chimaeric genes), or insertional mutagenesis (e.g. viral infection)
2 examples of aberrant expression is gained in oncogenes
strong enhancer increases normal protein levels to point where they can’t be shut off; fusion to actively transcribed gene overproduces protein, or fusion protein is hyperactive (e.g. Philadelphia chromosome)
describe how Philadelphia chromosome doesn’t allow apoptosis
BCR (anti-apoptotic product) on chromosome 22 translocated in front of ABL (strong promoter) on chromosome 9, meaning cell doesn’t die as lots of anti-apoptotic signal
2 types of cell receptors in cell which are involved in signal transduction (proto-oncogenes)
tyrosine kinase receptor, G-protein coupled receptor (triggers IC kinase cascade)
examples of tyrosine kinase receptor phosphorylation cascade proto-oncogenes
met, neu, src, ret
examples of G-protein coupled receptor phosphorylation cascade proto-oncogenes
ras, gip-2, raf, Pim-1
examples of transcription level modulator proto-oncogenes
myc, fos, jun
normal RAS activity to activate and inactivate RAF
to activate RAF, RAS is phosphorylated by GTP to form RAF/GTP dimer which activates downstream pathway; dephosphorylation of GTP to GDP switches RAS off
down-regulated RAS activity by cancer mutation
can’t bind GTP, so consitutively targeted by GDP, so downstream path not activated
mutant RAS aberrant activity by cancer mutation
fails to dephosphorylate GTP, so RAF constantly activated, so downstream path always activated
RAS signalling pathway
ligand binds to receptor -> tyrosine kinase phosphorylation -> effectors phosphorylated/dephosphorylated -> activation of MAPK -> activation of ERK -> transcriptional regulation effect in nucleus
tyrosine kinase proto-oncogene target
SRC (overexpression/C-terminal deletion)
2 transcription factor proto-oncogene targets
MYC (translocation) and JUN (overexpression/deletion)
2 G-protein proto-oncogene targets
Ha-RAS and Ki-RAS (point mutations)
