Flashcards in tumour biology/signalling/genomic instability Deck (36):
what does Rb control
the G1/S checkpoint.
must be phosphorylated by CDK4,6/cyclin D to release E2F which acts as a TF for S phase proteins
what does E2F do
activates transcription of itself and cyclin E/cdk2 which further stimulates Rb phos and more E2F.
overall the E2F coordinates regulation of genes that together promote entry into S phase
what happens when Rb/E2F binds DNA
recruits hisotne deacetylases and chromatin remodelling factors to the E2F responsive promoters to repress them
how many cancers does Rb disregulation occur?
almost all. but different players in the pathway in different cancers.
whats the pathway inc Rb and how can it be compromised at each stage
p16INK4a inhibits cyclinD+CDK4/6. it can be mutated, deleted or promoter hypermethylated (silences).
- cyclinD+CDK can be amplified
-Rb can be mutated or deleted
how does p53 work
short half life so normally low concs.
- DNA damage stablises it so conc rises.
-p53 acts as a TF for the CDKI p21CIP which inhibits almost all cdk/cyclin complexes.
- leads to G1 and G2 arrest.
if DNA damage is severe it can activate pro-apoptotic genes eg BAX
how many cancers have mutant p53
about half of all human cancers.
the bioactive form is a tetramer so mutating one allele sig reduces prob of a normal tetramer
what does the INK4a gene encode
2 potent tumour suppressors
the exon combination is different.
how is p53 activated in oncogene activation
ARF accumilates and activates p53 in response to abnormal proliferative signals such as oncogene activation.
- ARF accumilation sequesters mdm2 which would normally have targeted p53 for degredation.
what activates p53 in DNA damage
AT protein kinase inhibiting mdm2 and activating p53.
so what happens in general when p53 is mutated
cell can survive with oncogenes on and gene amplification.
what is essential to overcoming replicative senescence
deregulation of both Tb and p53.
phenotype of APC
100s of adenomatous polyps in the large intestine following inherited mutation of APC
describe the APC protein
cytoplasmic. mutated in most colonic adenomas and carcinomas.
- regulates Wnt signalling pathway, crucial in development and maintenance of tissue organisation. cell to cell signalling.
- control beta catenin levels by promoting its phos and degredation
what is beta catenin
a bi functional molecule.
- forms complex with e cadherin at plasma membrane in adherens junctions.
- in cytoplasm it is phosphorylated by GSK3beta and rapidly degraded by the proteasome.
- other regulatory proteins also act on beta catenin
Wnt signalling pathway
Wnt ligand binds receptors. intermediates inhibit GSK3beta.
- unphos beta catenin is stabilised, translocated to the nucleus, promotes transcription of growth genes (eg c-myc) via the TF TCF-4 (which is complexes with)
TCF-1 inhibits TCF-4
what is Wnt
a paracrine growth factor
what is the beta catenin/TCF complex
a master switch in intestinal crypts controlling prolif vs differentiation via c-myc etc
why do cells fail to die
- p53 inactivation
- telomerase activation
how do cancer therapies, radiation and chemo work in general
by inducing apoptosis.
in tumour cells at least one death pathway remains intact.
cancer mutation to block apoptosis targets what
- death receptors (fas, TNFR)
- activation of anti apoptotic protiens eg Bcl-2
- downregulation of proapoptotic proteins eg Bax and p53 (which activates Bax, PUMA, NOXA)
- doesnt target the caspases
why is genetic instability important in oncogenesis
normal to cancer reuires probably at least 6 mutations in a single cell, several in tumor suppressor genes hence needing to be in both alleles. for this to happen within a lifespan the mutation rate has to be sped up by acquisition of genetic instability, called by some 'the mutator phenotype'.
what is the evidence for genetic instability is malignant cells
- most solid tumours are aneuploid. abnormal numbers and arrangements.
- most have deregulated p53 which normally arrests the cell cycle to allow DNA repair
- mutations in DNA repair genes gives an increased susceptability to cancer.
the 4 known major DNA repair mechanisms
1 - DNA mismatch repair
2 - nucleotide excision repair
3 - DNA strand break repair
4 - fanconi anaemia repair
what does mismatch repair correct
- mismatched bases like C-t instead of C-G.
- insertion/deletion loops, commonly occur where short sequences are repeated ie CACACACA. microsatellite sequences. these occur often in the human genome.
what happpens when mismatch repair fails and when does it do so.
mutation rates rise 100-1000 times.
- genes: MLH1, MSH2. mutated in hereditary non-polyposis colorectal cancer (HNPCC). and 2-5% of all colorectal cancers such as lynch syndrome.
- also sporadic changes such as MLH1 silencing due to promoter methylation, found in about 15% of colorectal cancer.
name 2 things that NER repairs
crosslinked adjacent thymines crosslinked by UV light. or a carcinogen attached to a base.
what happens when NER fails
what does DNA strand break repair do
fixes double and single strand breaks which can be induced by ionising radiation, chemical carcinogens and sometimes in virally infected cells.
genes in DNA strand break repair
BRCA1 and BRCA2 in double strand break repair
whats fanconi anaemia repair
used for the repair od DNA intrestrand crosslinks eg by acetaldehyde (ethanol metabolite) or formaldehyde (smoking) which would otherwise block both transcription and replication.
mutations in the mechanisms lead to a range of cancers and fanconi anaemia
where do you find chromosomal rearrangements
in solid tumours, particularly extensive in carcinomas. the changes are not characteristic of a specific cancer except in the case of some leukaemias.
- rearrangements often involve tuour genes
how do aneuploidies arise
poorly understood but the loss of a functional p53 pathway is usually critical
what's an aneuploidy
an abnormal number of chromosomes
what are karyotypic rearrangements
structural rearrangements of the chromosomes.