Oncogenes Flashcards
Differentiation between a viral and cellular/proto oncogene
v- or c- prefix
Explain ras and what differs when ras is mutated
Ras is a GTPase Ras bound to GDP Activating signal incr GTP amount GTP displace GDP ras-GTP signal division ras breakdown GTP to GDP (in mutated ras this doesn't happen)
In what 6 ways can oncogene products exert their effect
1) Act like growth factors to stim cell division
2) act as GF rec expressed at cell mem
3) act in signal transduction
4) act to directly incr gene expression (are TFs)
5) normally repress growth but don’t when mutated
How do some oncogene products act in signal transduction
Respond to cell act by ligand-rec complex. Eg pro kinases phosph other pros to act/deact them further down cascade
How can oncogenes become disregulated
Gene amplification
Increased expression
Loss of control of function
Explain how oncogenes can become disregulated by gene amplification
Tumour cell is self-perpetuating, so select for any mutations that give growth advantage (so that incr cell prolif)
eg the myc gene becomes duplicated
If a gene is duplicated on one chromosome - have 50% more expression
Explain how oncogenes can become disregulated by increased expression
If gene is translocated to where there is a stronger promoter or when a viral promoter inserts into the chromosome (retrovirus) or if oncogene is inserted into viral genome or if promoter seq mutates and recognise different TFs that may be more abundant so express at the wrong time/level
Explain how oncogenes can become disregulated by loss of control of function
Mutation of Dna of oncogene so interact with other pros differently so can’t be inact or can’t be autocatylytically inactivated. Eg rec may mutate to be act w/out ligand, so can be permanently switched on
Eg ras mutation, src kinase mutation
Explain what occurs in src kinase mutation
A Tyrosine is not present so one of the phosphorylation events can’t occur so it is always active
Describe the role of inheritance in oncogene and antioncogene disregulation
Dominant traits are the result of mutations which disregulate oncogenes (so change in time of expression, function or IC conc)
Recessive are result of loss of genes encoding pps that repress cell growth (a-oncogene)
Antioncogene products
p53
Rb
Rb problems
2 mutant inactive copies assist with development of retinoblastoma - often inherit 1 mutant and other copy mutates during life
Rb fx
Bind many c-onc products which effect the nucleus and so prevent these products incr transcription
Block S-phase entry
p53 problems
Abnormality appears to aid tumour survival
Can behave as a dominant oncogene able to immortalise primary cells & can co-op with active ras genes to transform them
Mutant presence correlate with tumour invasiveness and aggression
p53 fx
Role in directing cells toward apoptosis (when enviro and pros present not right)
Overexpression of 1 good copy can inhibit oncogenic property of mutant
Dna damage causes
Chemical
Physical
Biological
Chemical dna damage
Carcinogens (often not original chemical but a metabolite)
Physical dna damage
Ionising radiation
Asbestos
Biological dna damage
Bio agents administered inappropriately eg cytokines, steroids
Viruses
What is an oncovirus
RNA tumour viruses (all known are retroviruses)
How do oncovirus cause cell transformation
Many mechanisms but all mediated by c-oncogenes
Must either express oncogene in its genome or influence expression of a pre-existing c-onc
DNA tumour viruses
Transforming genes are key to viral growth, with no close cellular homologue. Mech of action reflects role in viral growth cycle.
Carcinogenesis
Multistage process
Virus may interact with cell factors to fully transform a cell or a viral induced benign tumour may be acted on by other factors to cause malignancy
