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BMS247 Stem Cells > L14/15 - Check Point Controls > Flashcards

L14/15 - Check Point Controls Flashcards

1
Q

Getting genetic material from one cell to the daughters depends on

A

Faithful replication of a cells geneome

Proper allocation of the cells DNA to the daughter cells

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2
Q

Cells are only allowed to proceed with the cell cycle if …

A

If the pre-requisites have been completed sucessfully

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3
Q

What happens if the pre-requistes have not been met

A

Halt to further advance until the problems have been adressed

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4
Q

The monitoring of cells are known as

A

Check point controls

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5
Q

What is the result of a cells genome being in need of repair

A

The cell will not be able to enter S phase

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6
Q

What hapeens if DNA is damaged

A

Replication will be paused

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7
Q

What happens if the G2/M checkpoint if there is DNA damage

A

Entry into M phased is blocked

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8
Q

When is a cell allowed to enter anaphase

A

When all of its chromosomes are properly alligned on the mitotic spindle during metaphase

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9
Q

What monitors each step of the cell cycle

A

Surveillance mechanisms

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10
Q

What happens if the pre-requiste steps havent been met

A

Halt to further advance until problems have been adressed

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11
Q

What must be the state of the genome for the cell to be able to proceed into S phase

A

Genome is not in any need of repair

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12
Q

When may DNA replication be paused

A

If there is damage to the DNA

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13
Q

If cell needs to pause replication of the DNA what is the effect of this on the duration

A

Can double the time taken for the genome to be replicated

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14
Q

What must be completed for a cell to proceed through G2 and M phase

A

Replication of the DNA

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15
Q

M phase entry will be blocked if

A

DNA damaged

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16
Q

A cell is not permitted to enter anaphase until ….

A

All of its chromosomes are properly assembled on the spindle during metaphase

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17
Q

How does the increased mutability of the genome provide cancer cells with a prolfierative advantage

A

Incompatible with normal cell cycle progression

Checkpoint controls block advance through the cell cycle if DNA has been damaged

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18
Q

In addition to activating oncogenes and inactivating tumour supressor genes what else may be inactivated

A

One or more check point controls

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19
Q

pRB ….

A

Blocks advance through the cell cycle

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20
Q

What is the molecular goveronor of the R point

A

RB (retinoblastoma)

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21
Q

Cells are only able to go through the R point only if …

A

pRb becomes hyperphosphorylated

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22
Q

pRb phosphorylation is governed by

A

Components of the cell cycle clock

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23
Q

pRb becomes phosphorylated in what phase …

What complex mediates this

A

D-CDK4/6

Early and mid-G1

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24
Q

Levels of what cyclin increase at the R point

A

E

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25
Q

What complex mediates the hyperphosphorylation of pRB

A

E-CDK2

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26
Q

Unphosphorylated/hypophosphorylated pRB is able to bind to

A

E2F

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27
Q

When hyperphosphorylated what happens to Rb association with E2F

A

Dissociates

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28
Q

Describe the effect of pRb binding to E2F, and when does this occur

A

In early and mid G1 - pRb binds to E2F preventing the trasncription of E2F dep genes

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29
Q

pRb becomes hyperphosporylated at the R point - effect of this

A

Release of E2F

Transcription of genes which mediate the transition between G1 ans S phase

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30
Q

Why is the activity of E2F shortlived

A

Cyclin A-CDK2 inhibits the transcritpional activity of E2F - which is then tagged with ubiquitin and is degraded

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31
Q

Cyclin E transcription promotes driving of

A

E2F

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32
Q

What is the purpose of the spindle checkpoint

A

If a chromosome has been misplaced the cell cycle will be paused allowing time for the stray chromosome to be captured

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33
Q

Progression to anaphase controlled by

A

The anaphase promoting complex

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34
Q

APC/C

A

Anaphase promoting complex

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35
Q

When is the APC/C active

A

When all of the chromosomes are aligned on the spindle

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36
Q

APC/C is a

A

Ubiquitin ligase

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37
Q

What does APC/C ubiquitinate

A

Securin - causing the degradation of securine

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38
Q

What is securin bound to

A

Separase

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39
Q

When does separase become active

A

When securin has been ubiquitinated and degraded - and separase has been released from its complex with securin

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40
Q

What is the role of separase once it become active

A

Breaks the links between the 2 sister chormatids

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41
Q

How does separase break the links between the 2 sister chromatids

A

Degrades cohesin

42
Q

What is checked for at the G2/M transition

A

Integrity and fidelity of the DNA

DNA replication

43
Q

DNA damage checkpoints are active when

A

G1, S, G2

44
Q

What protein mediates cell cycle arrest when there is a double strand break

A

ATM

45
Q

What protein mediates cell cycle arrest when there is a single stranded break

A

ATR

46
Q

P53 is a

A

Tumour suppressor gene

47
Q

What molecular function does P53 have

A

It is transcription

48
Q

What genes are regulated by p53

A

Genes which mediated growth suppression, apoptosis and repair

49
Q

What is the target gene of P53

A

P21(Cip1)

50
Q

P21 is a

A

CKI

51
Q

What does P21 inhibit

A

E-CDK2, A-CDK2, A-CDC2 and B-CDC2

52
Q

Describe the normal mechanism of function of P53 in response to dNA damage

A

P53 detects DNA damage and activates transcription of target genes

  • Cells halt at G1 checkpoint
  • DNA repair activated
  • Apoptosis
53
Q

The underlying concept in P53 in response to DNA damage

A

Damaged DNA is not passed on to progeny

54
Q

An effect of a mutation in P53 means that

A

P53 is unable to bidn to the DNA so can’t transcribe any of the genes

55
Q

What is the outcome of mutation in p53

A

Damaged DNA is passed on

56
Q

What is anoikis

A

Cell detachement induced apoptosis

57
Q

What is the point of anokisis

A

A self defence stratergt that organsisms use to eliminate cells in inapproporiate locations

58
Q

Myc protein governs

A

The deicsion of proliferation vs differentiation

59
Q

More that 70% of human tumours overexpress

A

A member of the myc family

60
Q

What are the members of the myc family

A

C/N/L myc

61
Q

How many ways of myc inductions

A

3

62
Q

Describe breifely the three ways of myc induction

A

Expression dirven by a normal promoter but gene is amplifed due to an abnormal copy number

Chromosomal translocation - puts myc under control of a foreign promoter

Pro-virus integration causes insertional mutagenesis

63
Q

What type of molecule is myc

A

bHLH TF

64
Q

Describe the strucutre of myc

A

basic DNA binding domain followed by an amino acid sequence forming an alpha helix, a loop and then a second helix

65
Q

Myc forms …… which then becomes associated with gene promoters

A

Dimers

66
Q

What is the effect of myc-max on proliferation

A

Promotes

67
Q

What is the effect of myc-max on differentiation

A

Inhibits

68
Q

What is the effect of mad-max on proliferation

A

Inhibition

69
Q

What is the effect of mad-max on differnetiation

A

Promotes

70
Q

Mad is expressed more highly in what cells

A

Differentiating cells

71
Q

The higher levels of expression of Mad in differentiating cells means

A

Mad able to dispalce myc from its complex with Max

72
Q

What does myc/max also regulate

A

The expression of key componenets of the celll cycle including C2 and CDK3
Also has an effect on E2F transcription facotrs

73
Q

What is the effect of myc-miz1

A

Repression of CKI liberating E/CDK2 complexes from inhibitio n

74
Q

What is the effeect of myc-miz1 on P27

A

Deg

75
Q

Describe an experimental set up of the Myc oncoprotein

A

Myc expressed as a fusion protein with oestrogen receptor

Addition tamoxifen or oestrogen (ligand) drives myc translocation to the nucleus

76
Q

What is the effect of adding tamoxifen to cells that are in G0 in the absence of any growth factors

A

tamoxifen addition induces re-entry back into G1 and S phase

77
Q

The conclusion of the ‘powers of myc protein’

A

Myc is acting on its own and is able to lift all of the constraints on proliferation

78
Q

What is TGF-B involved in

A 
Growth 
Differentiation 
Apoptosis 
Homeostasis 
Other cellular functions
79
Q

What receptor does a TGF-B ligand bind to

A

Binds to the type II receptor which then recruits and phosphorylates the type 1 receptor

80
Q

Type 1 receptor phosphorylates

A

Receptor regulated SMADs

81
Q

What can happen once the type I receptors has phsophrorylated the R-SMADs

A

Can then bind to the coSMAD - SMAD4

82
Q

TGF-B strongly increases levels of …..

This causes ….

End result of this is that ….

A

Levels of P15

Inhibition of C-CDK4/6

Cells are unable to reach the R point

83
Q

TGF-B weakly induced

A

Levels of P21

84
Q

TGF-B uses ____________ to block progression through

A

2 CDK inhibitors (p15 and p21) to block progression through G1

85
Q

TGF-B inhibits the expression of

A

Myc

86
Q

Is TGF-B still able to inhibit the expression of myc in tumours

A

No

87
Q

TGF-B _________ the activty of Myc

It also stops the binding of _______ to CKI promoters

A

Counteracts

Myc

88
Q

What are two examples of how cancer cells inactivate TGF-B signalling

A

Mutations in SMAD4

Mutations in colon cancers

89
Q

TGF-B inhibits cell cycle progression by controlling pRb function

How do cancer cells get aorund this

A

Deregulation of the pRB pathway

90
Q

What are the mechanims of deregulation of the pRB pathway

A

Inactivation of Rb through mutations
Expression of very high levels of cyclin D1
Downregulation of INK4 proteins - inapproproate activation of pRb
Mutations in CDK4 gene - no longer able to bind the INK4 familty

91
Q

P53 is a TF for genes

A

Regulating cell growth and apotosis

92
Q

P53 is the most …

A

Freuqentyl mutated gene in human cancers

93
Q

Where do mutations in p53 tend to occur

A

In the DNA binding domain

94
Q

Control of p53 levels is through _____

A

Mdm2

95
Q

Describe how p53 is controlled by Mdm2

A

Ubiquinated by Mdm2 and degraded by the proteaosome in the absence of stress

96
Q

When does Mdm2 cause the degradation of p53

A

When there is no stress

97
Q

What must happen when there is stress or damage

A

P53 must be protected from degradation

98
Q

What is the mechanism for the protection of P53

A

Phos of P53 blocks Mdm2 binding and this is mediated by ATM/ATR/Chk2

99
Q

What mediates all 3 of the DNA damage checkpoints

A

P53

100
Q

Describe what must happen to P53 when there is stress of damage

A

P53 must be protected
Phos of P53 blocks Mdm2 binding
ATM phos Mdm2 –> inactivating Mdm2
Rapid increase in p53 levels

101
Q

What is the effect of mitogenic and cell curvival signals

A

Induction of Mdm2
Phosphorylation induced activation of mdm2 (at a different residue
P53 is degraded in the proteasome
Supression of P53 levels

102
Q

How does p53 cause cell cycle arrest

A

By upregualting P21 which inactivates cyclin-CDK complexes

BMS247 Stem Cells (14 decks)

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