Cancer 10: Oncogenes and tubour supressors Flashcards
What are the hallmark of canceer?
Activating invasion and metastasis, evading growth supressors, enabling replicative immortality, angiogenes, resisting sell death and sustaining prolifferative signalling
How does the cell decide when cell cycle happens?
Cycle checkpooints-growth arrest to ensure genetic fidelity
At G1-S-if senses damages via p53
If DNA has been replicated well -G-S-
During replication-as cytoskeleton binds chormosomes check if binding is correct
What are oncogenes and protooncogenes?
Proto-usuallt essential proteins involved in cell growth, division and differentiation
mutation converts them to oncogene, whose protteins productrs no longer respond to influences
oncogenes can be abberently expressed, over expressed OR abberrantly active
single point mutations can be enough (but deletion (of regulatory sequence/domain)-
Can be amplified (Her2 in breast)
Chromosomal translocation-chimeric genes (Eg BCR-ABL)
What do everypart of a signalling cascade have in relation with cancer?
all proto-oncogenes
Either GCPR or TKR-
TKR-pass phosphorylation around-ususally leading to proliferation
GCPR-usually via cAMP or PLC-then leading to phospho cascade
Also nuclear or cytosolic receptor
Can be consitutitionally activated
eg: Met/Neu (TYR-Her1/2/3), SRC and Ret (present in many cancers-present in the phospho cascade-can start it without signal), Ras, gip2 (in the GCPR cascade)-
because all have so many roles cant just target one gene to have an effect-further downstream means better chance to make a “silver buller”
How is mutant ras related to cancer?
RasGDP gets phospho to RasGTP-activates RAF-MEKKK-MEKK-MEK-ERK-activate c-myc leads to proliferation
Mutatuion often lead to over activation-constitivly active-idenpendent of signal and mutant Ras fails to dephosph
What are the 5 main oncogenes and which cancer are they related with?
SRC-TKR-breast colonm lung-cterminal deletion Myc-TF-Burkitts lymphomas-transolcation JUN-TF-LUNG-overexpression Ha-RAS-bladder-point mutation Ki-Ras-colon, lung-point mutation
with same mutations, it can have different effects (Kras in lung is very bad-cant be targetted, but in colon can be targetted)
What are tumour supressing genes?
Genes whos protein function is to regulate cellular proliferation and maintain cell intergrity
Each cell has two copies-
Mutation/deletion of one copy is usually not enough–two hit hypothesis (even if people have pre-disposition-need to acquire second mutation)
But loss of both is loss of control
need to be unlucky twice
What is inherited cancer suspecibility?
Family history related of cancer and earlier age
bilateral tumours in paired organs (cancer)
Synchronous/sucessive cancer
Tumours in several system in same mutation
Mutation inherited through germline
What is retinoblastoma caused by>
Can be unilateral or bilateral (usually genetic)-mutation of TSG-13q14-RB1
RB1 encodes nuclear protein that involves regulation ofc cell cycle
WHat are the functional classes of tumour supressor genes?
Fit in hallmark of cancer Regulate cell prol, cell integrity Regulate growt, cycle Nuclear TDF DNA repair protein Cell adhesion molecules cell death regulators
=> supress neoplastic phenotype
What are the 6 main tumour supressor genes and what cancer are they associated with
p53-Cell cycle regulator-MANY
BRCA1-Cell cycle regulatory-breast, ovarian, prostate
PTEN-Tyrosine and lipid phosphatase-prostate, gliobastoma
APC-cell signalling-colon
P16-cell cycle regualtor-colon and more
MLH1-mismatch repair-colon, gastric
What is the role of p53?
Has so many role-why it cant be targetted for cancer because it has so many effects
Need to find if driver mutation or passenger
p53 causes DNA repair, growth arrest, senescence, apoptosis
Usually partnered with MDM2-which inhbits it-in high oxidative stress, p53 upregulated itself
p53 mutations are dominant and a single copy can be enough-present with rare tumours, very early
What is the role of the APC TumourSupressorG in cancer?
Driver of FAP-
Due deletion which causes loss of APC gene-lose anaphase regulating gene (and has role in cell mobility), and has role in MAPK pathway
colon has numerous polyps but 90% developing colorectal carcinoma
APC Works via WNT signalling pathwat-negative regulator of B-catenin (adhesion molecule and proliferation)
B-cateninin would activate if not inhbited-loss of APC means b-catenein always active
How do protooncogenes and tumour supressor genes combine to cause cancer?
Normally balance
But if proto starts to become oncogene-TSG are there to stop it
If TSG goes wrong-protooncogenes are still working fine so dont need supression
TSG are like breaks and onco are accellerator
If lose breaks and push on acellerator-cancer
Describe the development of colorectal cancer?
start with normal epithelium
Unsure if APC or Kras first-but leads to hyperproliferative epithelium-inherent mutation risk
To become adenoma-need the other (KRAS or APC)-low risk adenoma
Then lose things like p53 or other-cause carcinoma
But in some people, p53 happens early
hyperplasia, metaplasia, dysplasia, canrinogenesis
