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Biology of stem cells, ageing and cancer > Cell cycle regulation > Flashcards

Cell cycle regulation Flashcards

1
Q

What is cell cycle machinery influenced by?

A

cancer associated proteins
oncogenes
tumour suppressors

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2
Q

Restriction point

A

between G1 and S
cell is fully comitted and continues cell cycle without any extrinsic factors

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3
Q

CDKs

A

cyclin dependent kinases
deployed by cell cycle machinery
depend on accessory proteins called cyclins

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4
Q

CDK/cyclin complexes

A

responsible for sending out signals to the proteins that carry out work to move cells through the cell cycle

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5
Q

Why are cyclins needed for CDKs to perform their function?

A

cyclins activate catalytic activity of CDK partners
cyclins help with substrate recognition of the complexes in the cell

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6
Q

What does cyclin B pair with?

A

CDK1

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7
Q

What does cyclin D pair with?

A

CDK4/6

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8
Q

What does cyclin E pair with?

A

CDK2

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9
Q

What does cyclin A pair with?

A

CDK1/2

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10
Q

What happens to cyclin levels as the cell cycle progresses?

A

falls due to ubiquitin dependent degradation

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11
Q

What are D cyclins regulated by?

A

growth factors
integrin mediated ECM attachments

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12
Q

What does the removal of growth factors lead to?

A

rapid collapse of cyclin D1 levels

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13
Q

What cancers is cyclin D1 shown to be everexpressed in?

A

breast
lung
melanoma
oral squamous cell carcinomas

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14
Q

What does the over expression of cyclin D1 in pancreatic cancer cells cause?

A

increased cell proliferation
increased anchorage independent growth
reduced chemosensitivity and elevated survival in the presence of cisplatin

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15
Q

shRNA effect on cyclin D1

A

partially reduces protein expression in gastric carcinoma cells + reduced cell proliferation in vitro
decreased tumour formation
induction of apoptosis due to G1 arrest

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16
Q

What is the role of cyclin E?

A

phosphorylation of substrates required for entry into S phase

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17
Q

What happens when cyclin E1 is overexpressed?

A

found in many different tumour types, oncogenic role in ovarian cancer
associated with increased mRNA expression
occurs in early lesions

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18
Q

What does cleavage of cyclin E result in?

A

expression of low molecular weight cyclin E
- stable protein with a high affinity for CDK2
observed in cancer + resistance to therapy

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19
Q

What factors in normal cells control cell cycle progression?

A

mitogenic signals promote
TGF-b inhibits it

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20
Q

How is TGF-b involved in carcinoma pathogenesis?

A

strongly increase levels of P15
inhibits cyclin B CDK4/6 complexes so cells can’t reach the R point

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21
Q

What does weak induction of P21 lead to?

A

stronger induction upon DNA damage
cell cycle is halted until genome is repaired

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22
Q

How do mitogenic factors progress the cell cycle?

A

Akt phosphorylates p21 in the nucleus and it is translocated to the cytoplasm
Akt phosphorylates p27 in the cytosol which prevents nuclear translocation

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23
Q

What are mitogenic factors?

A

small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division
Akt

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24
Q

What does p27 mis-localisation lead to?

A

clinical progression when p27 was localised in the nucleus only

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25
What makes a patient more likely to have a more invasive cancer?
cytoplasmic p27 as it is used as a prognostic marker
26
Checkpoints
surveillance mechanisms to monitor each step of the cell cycle progression
27
G1/S checkpoint
cell will not be permitted to enter S phase if the genome is in need of repair
28
S checkpoint
DNA replication will be paused in response to DNA damage (this can cause the doubling of the time required to complete DNA synthesis)
29
G2/M checkpoint
a cell will not process through G2 to M until the DNA replication of S phase has been completed and entrance in M phase is blocked if the DNA is damaged
30
Spindle assembly checkpoint
a cell is not permitted to enter anaphase until all of its chromosomes are properly assembled on the mitotic spindle during metaphase
31
How do cancer cells have proliferative advantage?
- incompatible with normal cell cycle progression - checkpoint controls block advance through the cell cycle if DNA has been damaged
32
pRb
nuclear phosphoprotein absent/present in a defective form in many tumours molecular governer of the R point
33
How does pRb govern the R point?
cells can only go through if pRb becomes inactivated through hyperphosphorylation when un/hypophosphorylated it binds to E2Fs, when hyperphosphorylated it dissociates
34
How is pRb phosphorylation tightly controlled?
- early and mid G1 → D type cyclin and CDK4/6 initiate pRb phosphorylation - cyclin E levels increase at the R point → cyclin E/CDK2 mediate pRb hyperphosphorylation
35
How does pRb in early-mid G1 prevent cell cycle progress?
pRb binds to E2Fs preventing the transcription of E2F-dependent genes decrease in trasncription of genes needed for S phase
36
pRb at the R point
pRb hyperphosphorylation → E2Fs are released → transcription of genes mediating G1/S transition
37
How is active transcription promotion by E2Fs short lived?
begins at the R point (pRb hyperphosphorylation) during G1/S transition cyclin A/CDK2 inhibits the transcriptional activity of E2Fs they are then targeted for degradation by ubiquitination
38
How does E2F expression lead to positive feedback loops?
cyclin E transcriptionn E-CDK2 mediates the phosphorylation of p27kip1 which leads to its degradation more E-CDK2 released from inhibition
39
What are the three mechanisms of pRb inactivation observed in human cancers?
RB1 gene mutations inactivation by deregulated phosphorylation interaction with viral proteins
40
How do RB1 gene mutations inactivate pRb?
directly affect pRb function by either completely abrogating its expression or by producing a non-functional protein
41
How does interaction with viral proteins inactivate pRb?
E7 produced by HPV displaces E2F from pRb → uncontrolled cell proliferation in cervical cancers
42
Why are cyclins difficult pharmacological targets?
no kinase activity and intracellular localisation
43
Inhibition of what has therapeutic value as an anti-cancer treatment?
cyclin-D dependent kinase
44
Palbociclib
potent selective inhibition of CDK4 and CDK6, comptetitive with ATP - inhibition of breast cancer cell growth in vitro - no effect on normal cells
45
CDK4/6i treatment
approved for treatment of hormone receptor positive breast cancers, all patients with metastasis will develop resistance
46
CDK4/6i inhibitor resistant cells show...
overexpression of cyclin E and cMYC
47
What are cyclin E overexpressing tumours sensitive to?
CDK2/4/6i
48
What influences contribute to DNA damage?
- incomplete DNA replication due to stalled replication forks and reactive oxygen species - UV light - ionising radiation - DNA damage chemotherapeutics
49
DDR
complex network of signalling pathways which monitor DNA integrity in case of DNA damage activates cell cycle arrest and DNA repair to ensure maintenance genomic stability
50
How is DDR inactivation a hallmark of cancer?
associated with transformation and contributes to carcinogenesis by increased genomic instability defects in DDR render cancer cell more dependent on the activity of the remaining intact DDR and susceptible to therapies
51
What 3 components are implicated in the initiation of DDR?
PI3K ATM ATR
52
ATM
activated by DNA double strand breaks key role in the activation of the G1/S checkpoint preventS cells with damaged DNA from entering S phase
53
ATR
activated by DNA single stranded breaks at stalled replication forks/replicative stress plays a role in the S phase checkpoint key mediator of the G2/M checkpoint prevents premature entry of cells into mitosis before DNA duplication is completed/DNA damage present
54
WEE1
involved in S and G2/M checkpoints by regulating CDK activity
55
Replicative stress
stalling or slowing of replication fork progresion and or DNA synthesis during DNA replication
56
What can cause replicative stress?
oncogenic signalling insufficient levels of DNA replicating enzymes/nucleotides inactivation of TSGs
57
CHK1
cell cycle checkpoint kinase 1 (CHK1) shows significant cellular cytotoxicity when depleted potential therapeutic target for neuroblastoma
58
What happens when myc overexpression causes replicative stress?
activates ATM/ATR-CHK1 dependent DNA damage response
59
CHK1 mRNA
expressed at a higher level in MYCN-amplified tumours in high risk tumours compared to low risk ones
60
bHLH transcription factors
basic DNA binding domain followed by amino acids sequences forming an alpha helix, a loop and a second alpha helix members of the the bHLHL family form dimers → association with gene promoters
61
Myc-max complexes
promotes proliferation and inhibits differentiation
62
Mad-max complexes
inhibtis proliferation and promotes differentiation
63
What does myc accumulate in the presence of?
mitogens
64
What components of the cell cycle clock does myc-max regulate?
cyclin D2 and CDK4- elevates expression leading to pRb hypophosphorylation E2F transcription factors
65
Myc-miz1
repression of the transcription of CKl, liberating cyclin E/CDK2 complexes from inhibition myc also promotes the degradation of p27 → progression through the R point
66
What happens when myc is expressed as a fusion protein with oestrogen to translocate into the nucleus?
cells in G0 in the absence of growth factors then are induced to enter G1 and S phase - myc acting on its own is able to relieve all of the constraints on proliferation
67
Direct myc inhibitors
block the dimerization of myc and max or can interfere with the binding of the dimers with DNA
68
Indirect myc inhibitors
interfere with myc expression at a transcriptional level or at the level of protein turnover or they target transactivation function of myc
69
Myc inhibition
results in tumour regression in mouse models on pancreatic cancer
70
TGF-b
signalling pathway involved in many cellular processes (cell growth, cell differention, apoptosis & cellular homeostasis  
71
TGF-b mechanism
ligands bind to a type II receptor which recuits and phosphorylates type I receptor this then phosphorylates receptor-regulated SMADs which can now bind SMAD4 R-SMAD/SMAD4 complexes accumulate in the nucleus where they act as TFs
72
What is the role of TGF-b in the cell cycle?
stongly increases levels of p15INK4B -> inhibition of cyclin D-CDK4/6 complexes -> cells can't reach R point weak induction of p21
73
TGF-b and myc
counteracts the activity of myc inhibits the expression of myc and prevents myc from binding CKI promoters
74
TGF-b and myc
counteracts the activity of myc inhibits the expression of myc and prevents myc from binding CKI promoters
75
How do some cancers inactivate TGF-b signalling?
½ pancreatic carcinoma and ¼ colon cancers = inactivated (mutant) Smad 4 -> TGF-b signalling is compromised
76
What cancers have been identified as having SMAD2 mutations?
colorectal cancer and lung cancer
77
In what cancers is SMAD3 expression lost?
gastric cancers
78
What cancers show a reduction in TGF-bR expression/activity?
colon pancreas ovarian breast
79
How does tumourigenesis convert TGF from a tumour suppressor to a tumour promoter?
disregulated myc expression counteracts TGFB inhibition of cell cycle progression hyperactivation of PI3K/AKT pathway inactivates cytostatic activity of TGFB
80
How does stimulating cancer cells with TGFB lead to the ability to increase proliferation?
TGFB dependent expression of cytokines and GFs and their receptors
81
Epithelial to mesenchymal transition
process through which polarised epithelial cells are converted into motile fibroblast-like cells essential for cancer cell invasion & metastasis TGF is a master regulator
82
Compounds targeting TGFB signalling
Antisense oligonucleotides Neutralising antibodies blocking ligand/receptor interaction antibodies that sequester ligands Receptor kinase inhibitors
83
What cancers are reduced by TGFB kinase inhibitors and neutralising antibodies?
inhibits lung and bones metastasis doesn't affect survivial of glioma patients
84
What cancer is reduced by TGFB2 anitsense oligonucleotides?
increased high grade glioma patients survival
85
What causes p53 induction?
lack of nucleotides UV radiation, ionizing radiation oncogene signalling hypoxia blockage of transcription
86
What happens when there is a rapid increase of p53 protein levels?
no difference in mRNA levels post translational stabilisation of p53
87
How is p53 degraded in absence of stress?
ubiquitinated by Mdm2 and degraded by the proteosome
88
How is p53 protected from degradation when there is stress or damage?
phosphorylation of p53 blocks Mdm2 binding mediated by ATM/ATR/Chk2 ATM can phosphorylate Mdm2 which leads to inactivation
89
How do mitogenic and cell survival signals affect p53 levels?
phosphorylation induced activation of Mdm2 p53 proteosomal degradation
90
p53 cell cycle regulation
arrests cell cycle primarily by upregulating p21 this inactivates cyclin CDK complexes

Biology of stem cells, ageing and cancer (5 decks)

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