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Tumour Suppressors Flashcards

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1
Q

what are tumour suppressors

A

gene products that can suppress or block the start/ development of cancer

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2
Q

what does a mutation of a tumour suppressor cause

A

loss/ reduction in tumour suppressor function and in some cases gain of oncogenic functions that permits the cell to progress to cancer

(this is usually in combo with other genetic changes)

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3
Q

name two tumour suppressors

A

Rb (retinoblastoma)

P53

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4
Q

what are the basic functions of Rb and P53

A

Rb - cell cycle regulation

P53 - cell cycle and survival regulation

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5
Q

are tumour suppressors dominant or recessive

A

recessive - need two inactivating mutations to functionally inactivate the gene

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6
Q

what is the two hit hypothesis

A

if you inherit one germ line mutation from your parents then you are more susceptible to a mutation in the other allele as there is a selective force driving loss of remaining allele (loss of heterozygosity)
need mutation in both alleles for loss of function of tumour suppressors

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7
Q

are germ line or somatic mutations inherited

A

germ line

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8
Q

what is haploinsufficiency

A

when loss of one copy of a gene is sufficient to permit development development of the disease

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9
Q

what is mutates in li fraumeni syndrome

A

p53

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10
Q

what check points does Rb regulate

A

G1-S

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11
Q

what cyclin is needed for progression through the G1 S checkpoint

A

cyclin CDK

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12
Q

what checkpoints does p53 regulate

A

G1/S
S phase
G2/M

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13
Q

what is E2F-DP1

A

transcription factors that form a heterodimer and induce transcription of genes required for DNA synthesis drive S phase)

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14
Q

what is the relationship between Rb and E2F-DP1

A

Rb binds to the heterodimer and inhibits it from functioning so that genes required to drive the S phase aren’t transcribed

it does this by recruiting HDAC-SWI/SNF complex

=stops the transition from G1 to S

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15
Q

what does RB bound to E2F-DP1 and HDAC-SWI/SNF prevent

A

prevents progression orm G1 to S by stopping E2F-DP1 transcription factors promoting genes that drive S phase

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16
Q

summaries the MAP kinase signalling pathway

A

receptor tyrosine kinase - Ras- Raf- mek- erk - transcription factors

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17
Q

what is cyclin D1 gene

A

an oncogene

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18
Q

what does cyclin D do

A

allows cell to go into the S phase by phosphorylating Rb
this releases RB from the E2F-DP1 and HDAC-SWI/SNF complex
this allows transcription of critical genes and the cell to enter S phase

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19
Q

phosphorylation of what is essential for the G1 -> s transition

A

Rb (by cyclin D)

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20
Q

what can inactivate Rb

A

mutation (stops it binding to E2F-DP1)
or by certain viruses (SV40, T Ag)

(remember inactivation means no longer working as tumour suppressor so increased trasncrption)

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21
Q

what genes are expressed in S phase

A

DNA synthesis genes

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22
Q

what checkpoint does mutation of Rb eliminate

A

G1-S checkpoint

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23
Q

what does a loss of heterozygosity mean for tumour suppressor

A

means that remaining working tumour suppressor has gained a mutation, inactivating it like the other already inactivated allele- double hit

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24
Q

what is p53

A

short lived tumour suppressor that is stabilised and activated by various stress stimuli

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25
what is the main function of p53
transcription factor
26
what is the result of transactivation of p53
apoptosis or survival: cell cycle arrest, senescence, genome instability, repair, metabolism, autophagy, repair DEPENDS ON WHAT STRESS SIGNAL, THE DURATINO OF THE SIGNAL AND OTHER GENES BEING EXPRESSED ALREADY IN THE CELL
27
what activates p53
stress signals
28
what are the functional domains of p53
N terminus has 2 transactivational domains responsible for transactivation of expression of target genes DNA binding domain tetramerisation domain and regulatory domain towards C terminus
29
how does p53 act as a transcription factor
binds as a tetramer to consensus DNA binding sites upstream of its target promoters once it is bound recruits p300 which results in the acetylation of histones allowing transcription after recruitment of other transcription factors and RNA polymerase this allows the expression of p53 target genes
30
what is p300
histone acetyl transferase
31
what genes does p53 target
basal transcription factors - which genes it targets depends on the context of the cell
32
what does p53 orchestrate
changes in gene expression leading to cell cycle arrest or apoptosis
33
list the types of genes transactivated by p53
growth arrest genes e.g. p21 apoptosis genes e.g. NOXA, BAX, Fas, PIG3, PERP repair genes e.g. p53R2 metabolism genes e.g. TIGAR angiogenesis block genes e.g. maspin, TSP-1
34
what is MDM2
the autoregulatory partner of p53
35
what is the action of MDM2
once induced it binds to p53 and causes degredation (creating regulatory loop)
36
at what stages does p52 induce arrest
G1-S | G2-M
37
what does p53 target to cause arrest at G1-S
p21 -> cyclin CDK | p21 also works at G2-M checkpoint
38
what is p21
cyclin dependent kinase inhibitor
39
how does p53 control cell cycle
coordinating gene expression
40
what does p21 do
inhibits CDKs and causes block of G1-s
41
how does p53 cause apoptosis
induces NOXA, PUMA, BAX, AIP1, APAF 1 which leads to cytochrome C release as well as caspase 9 and then three 3 capase three cayses chromatin condensation, DNA fragmentation and surface alterations P53 also activates genes that activate caspase 8 which in turn activates capase 3
42
what is the warburg effect
observation that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol
43
how do most normal cells produce energy
low rate of glycolysis followed by oxidation of pyruvate in mitochondria
44
how does p53 prevent the warburg effect
blocks expression of genes e.g. TIGAR that cause this change in metabolism
45
list the mechanism of p53 activation
ARF pathway DNA damage pathways Nutlin (drug)
46
what triggers the ARF pathway (activating RAF)
oncogenes/ high proliferation | hypoxia
47
how does MDM2 regulate p53
promotes ubiquitylation and proteasomal degradation of p53 (normally keeps p53 at low levels) P53 induces the expression of MDM2 (MDM2 is an E3 ubiquitin ligase)
48
how does p53 activation happen
interaction between p53 and MDM2 is disrupted | stress signals release MDM2 from p53 and stabilises it
49
what does p53 bound to MDM2 prevent
further binding of p53 to p300 | means p300 cant be transactivates
50
what is transactivation
stimulation of the transcription of a gene by binding a gene at another locus (either virus or cellular protein)
51
how do stress signals release MDM2 from p53
induce protein kinases (e.g. ATM, ATR) that cause the phosphorylation of p53 at the N terminus or acetylation of the C terminus releasing MDM2 and allowing p300 to bind
52
what happens when p300 can bind to p53
other transcription factors can be recruited and DNA can bind to DNA
53
how does oncogene activation affect p53
activate it by inducing ARF (way of fighting cancer)
54
how does nutlin -3 activate p53
competitive inhibition with MDM2 (prevents it binding)
55
why do you need some MDM2
prevent excessive apoptosis
56
can restoring p53 regress cancer
yes- in animal models due to decreased proliferation, differentiation and markers of senescence
57
how does p53 mediate tumour suppression
VIA SENESCENCE
58
what is the most frequently mutated gene in cancer
p53 | prevalence varies in different types of cancers
59
what are the majority of TP53 mutations in tumours
missense (NOT deletions) usually within the DNA binding domain, DNA content is distorted locally or globally due to altered folding (means that these mutant proteins provide advantage to cancer cells)
60
what do cells with mutant p53 show
increased metastatic potential and invasiveness | resistant to some drugs
61
what do li fraumeni individuals inherit
germiline p53 missense mutations causing inherited predisposition to cancer
62
what do most p53 mutants in cancers acquire
oncogenic function
63
do you need to loose the other p53 allele if the first mutant gains oncogenic function
NO as they act dominantly
64
what will somatic and germline mutations of p53 have a selective drive for
loss of heterozygosity
65
what are neutral p53 mutations
where the p53 just looses its function
66
what is the action of mutant p53 that has gained oncogenic function
apart from not binding to the target genes it normally binds to, mutants will now have new set of transcriptional target genes, interact with different set of transcription factors, activate transcription of different set of genes that stimulate proliferation (cyclines, CDK) and metastasis (phospholipase) they can also target genes that mediate inflammation (NFkB pathway) which prolongs stabilisation (increased stress factors) can also target genes for chromatin modifying enzymes which leads to global chromatin remodelling
67
why does mutant p53 accumulate in cancer cells
as mutant proteins dont induce expression of MDM2 so cant be degraded
68
how can p53 be inactivated in cancer
over expression of MDM2 (even if you have wildtype p53) via WIP1 phosphatase or inactivation of ARM/ARF
69
what does the mutation (or virus) of Rb cause
affects its ability to bind to HDAC-SWI/SNF or E2F-DPI, allowing cell to go through G1-S checkpoint
70
how does HPV cause cervical cancer
block Rb and p53 function | by E7 which blocks Rb and E6 which degrades p53
71
why do genotoxic drugs cause chemo side effects
as in normal cells that already have p53 working will cause the DNA damage caused will induce p53 causing growth arrest (protect against cancer) but also apoptosis (hair loss, nausea, memory loss)
72
how is p53 involved in chemo (genotoxic drugs)
drugs cause DNA damage induces p53 in tumour cells lacking p53 DNA damage enough to kill cell anyway as try to divide without checkpoint
73
what is p53 gene therapy
Advexin is a replication-defective adenoviral vector containing the wild-type human p53 cDNA under the control of the cytomegalovirus immediate-early promoter. Virus infects cells and results in expression of p53 in these cells
74
how does nutlin-3 restore p53 activity
competitive inhibitor of p53 binding to MDM2 (no genotoxicty- is tolerated in normal cells) (can also sensitise cancer cells to chemo and radio)
75
what is PRIMA-1
reactives mutant p53 by restoring native folding conformation (selectively works on mutant p53 not wild type)
76
what does cyclin D do
gene responsible for driving the cell from G1 in to S phase
77
how does Rb affect cyclin D
Rb stops its transcription when activated
78
do oncogenes drive the transcription of cyclin D
yes
79
what does cyclin D/ cdk 4/6 do to Rb
phosphorylates it, releasing it from its complexes | this allows E2F-DP1 to transcription genes promoting cell into S phase
80
how do viruses affect Rb
stop it being able to bind to complexes, these dimers without Rb transcribe DNA synthesis genes
81
what happens when transcription factors bind to p53
recruits transcription initiation complexes which are needed for transcription e.g. p300
82
what does p300 do
is a histone acetyl transferase adds acetyl groups to histones and the net effect is the histones open up, allowing the DNA to unwind enough to be replicated- acetylation of histones is needed to allow DNA transcription
83
where does p300 and p53 usually bind
p53 binds upstream to a promoter | p300 binds to DNA binding domain of p53
84
how does p53 affect the warburg effect
blocks it (by inducing genes e.g. TIGAR, and blocking other genes e.g. NF-kB)
85
how do stress signals affect p53
stops their degradation by preventing the interaction of p53 and mdm2 does this by phosphorylating p53 at the N terminus
86
how does mdm2 affect p53
``` degrades it (ubiquitylation and degredation) stops other things binding to it (p300) ```
87
what happens to p300 when there is DNA damage
p300 is needed normally for transcription, in DNA damage no different expect it binds to p53 to transcribe genes needed for cell arrest/ dna repair e.g. p21
88
how does p53 bind to dna
as a tetramer
89
what does ARF do to MDM2
binds to it and takes it away from p53, sequestering it in nucleolus, so that it cant interact with p53
90
what can cause over expression of mdm2
more copies of its gene | increased transcription of its gene
91
why is the use of an oncolytic virus risky
as once it is in there, if it doesnt agree with patient, cant get it out

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