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MIMS > Cell Cycle and Cell Death > Flashcards

Cell Cycle and Cell Death Flashcards

1
Q

how many cells are replaced in humans every day?

A

50 billion

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2
Q

what are the cells in the G0 phase typically like?

A

smaller with reduced metabolic activity

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3
Q

why will cells exit the cell cycle to G0?

A

if no mitogens are present

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4
Q

what causes cells to go from G0 to G1?

A

mitogens providing the stimulatory signal

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5
Q

what is the point of no return in G1?

A

START/the Restriction Point/Commitment Point- after which cell is committed to progression through cell cycle

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6
Q

what is important for cells to pass through START in G1?

A

hyperphosphorylation of RB family proteins by CDK4/cyclin D

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7
Q

what happens in S phase?

A

DNA replication

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8
Q

what happens in G2?

A

replicated DNA monitored, organelles replicated

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9
Q

what happens in the M phase?

A

cell undergoes mitosis and divides

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10
Q

what are the 3 checkpoints in the cell cycle?

A

G1/S, G2/M and spindle assembly checkpoint

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11
Q

what are the key molecular regulators of the eukaryotic cell cycle?

A

the cyclin-dependent kinases (CDKs)

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12
Q

what are the CDKs involved in G1?

A

CDK4 and CCDK6

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13
Q

what are the CDKs involved in G1/S and S?

A

CDK2

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14
Q

what are the CDKs involved in mitosis?

A

CDK1

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15
Q

what are the cyclins involved in G1?

A

cyclin D1. D2, D3

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16
Q

what are the cyclins involved in G1/S and S?

A

cyclin E

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17
Q

what are the cyclins involved in S phase?

A

cyclin A

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18
Q

what are the cyclins involved in M phase?

A

cyclin B

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19
Q

what is cyclin/CDK activity regulated by?

A

transcriptional control, ubiquitin mediated proteolysis, inhibitory phosphorylation, small CDK inhibitor proteins

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20
Q

which E2F transcription factors activate cyclin transcription?

A

E2F1, E2F2, E2F3

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21
Q

which E2F transcription factors repress cyclin transcription?

A

E2F4 and E2F5

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22
Q

what family of repressors regulates activity of E2F transcription factors?

A

the RB family

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23
Q

what does the RB protein do?

A

unphosphorylated RB binds to and inhibits E2F-dependent transcription, e.g. of cyclin E

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24
Q

what do p107 and p130 repress?

A

E2F4 and E2F5

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25
Q

what does Cyclin D-CDK4 phosphorylate and inhibit?

A

RB family proteins

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26
Q

what is addition of a covalently linked chain of Ub molecules to a protein a signal for?

A

for the protein to be degraded

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27
Q

what attaches ubiquitin to proteins?

A

the ubiquitine ligase complex APC/C-Cdh1

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28
Q

what is the APC/C complex?

A

anaphase-promoting complex/cyclosome

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29
Q

what does the ubiquitin ligase complex APC/C-Cdh1 do?

A

sticks ubiquitin onto proteins, degrades cyclin A and geminin in G1 phase (prevents premature entry into S phase)

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30
Q

what does the ubiquitin ligase complex APC/C-Cdc20 do?

A

degrades cyclin B in mitosis to allow chromosomes to segregate

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31
Q

which is a faster method of gene expression control, protein degradation or transcription regulation?

A

protein degradation

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32
Q

what protein is responsible for inhibitory phosphorylation of CDKs?

A

Wee1 kinase

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33
Q

when is inhibitory phosphorylation of CDKs particularly important?

A

the G2/M checkpoint

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34
Q

what is inhibitory phosphorylation of CDKs counteracted by?

A

Cdc25 phosphatase

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35
Q

which small CDK inhibitor proteins are particularly important for keeping cells in the G0/G1 phase?

A

p21, p27, p15/16

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36
Q

what does p21 inhibit?

A

Cdk2

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37
Q

what does p27 inhibit?

A

Cdk2

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38
Q

what does p15-INK4b inhibit?

A

CDK4/6

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39
Q

what does p16-INK4a inhibit?

A

CDK4/6

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40
Q

what are mitogens?

A

the cue that drives cell cycle progression

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41
Q

in what proportion of non-small cell lung carcinomas is EGFR mutated to be hyper-activated?

A

20%

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42
Q

in what proportion of human tumours are Ras mutations found?

A

20-25%

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43
Q

in what proportion of cancers is Myc overexpressed?

A

4%

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44
Q

how do cancer viruses override the G1 checkpoint?

A

express viral proteins that directly inhibit Rb

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45
Q

what is the function of myostatin as an anti-mitogen?

A

activates co-repressors of the SMAD family

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46
Q

what is the function of SMADs?

A

inhibit E2F target genes and activate CDK inhibitors like p15

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47
Q

what mutation do Belgian blue cows have?

A

mutations in the anti-mitogen myostatin, which functions to stop production of too much muscle, so Belgian blues have hyper-proliferation of muscle

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48
Q

what is Cyclin A/Cdk2 essential for in the cell cycle?

A

activating the DNA replication helicase and recruiting the polymerase to replicate the genome

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49
Q

what are Cyclin A/Cdk2 and geminin inhibitors of?

A

DNA replication helicase loading

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50
Q

what ensures the genome is only replicated once?

A

once initiation has begun APC/C is absent and cyclin A-Cdk2 is present, so no further helicase loading can take place

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51
Q

what does chromosome segregation require?

A

linkage between newly replicated sister chromosomes, alignment of linked sisters in the middle of the cell, chromosomes under tension

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52
Q

what are the ways newly replicated sister chromosomes are linked?

A

topologically intertwined, chromosome cohesion

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53
Q

how does topological linkage of sister chromosomes work?

A

DNA supercoiling during replication is resolved by the action of topoisomerases and rotation of the chromosome, leads to sisters intertwining

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54
Q

how does chromosome cohesion work?

A

caused by the cohesin complex- cohesin is a ring with a gap closed by Scc1

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55
Q

how are linked sister chromosomes aligned in the middle of the cell?

A

mitotic spindle machinery- microtubules from spindle to cell cortex, position spindle in middle of cell, kinetochore is where microtubules attach to chromosome

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56
Q

what region of the chromosome assembles the kinetochore?

A

the centromere

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57
Q

what is the MT organising centre?

A

centrosome

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58
Q

what mediates cleavage of cohesion once chromosomes aligned in middle of the cell?

A

separase- a protease

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59
Q

what causes separase to be inactive?

A

CDK phosphorylation and binding to inhibitor called securin

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60
Q

how does APC-Cdc20 activate separase?

A

degrades cyclin B and securin

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61
Q

when does separase cleave cohesin?

A

at the metaphase to anaphase transition

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62
Q

what are the phases of mitosis?

A

prophase, prometaphase, metaphase, anaphase, telophase

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63
Q

what happens in prophase?

A

chromosomes duplicated, cohesed and condensed. centrosomes move toward opposite poles, microtubules gradually assemble

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64
Q

what happens in prometaphase?

A

nuclear membrane breakdown allows spindle microtubules (MTs) to access the chromosomes. MTs attach to chromosomes at their centromeres via a protein complex called the kinetochore

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65
Q

what happens in metaphase?

A

chromosomes align along the cell equator, every chromosome has at least 1 microtubule connected to each centrosome

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66
Q

what happens in anaphase?

A

sister chromatids separate after breakdown of cohesin

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67
Q

what happens in telophase?

A

the chromosomes arrive at the cell poles, new nuclear membrane forms around each group of chromosomes

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68
Q

what happens in cytokinesis?

A

the physical process the splits the parent cell into 2 identical daughter cells

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69
Q

what activates the G2/M checkpoint?

A

incomplete replication

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70
Q

what do the G2/M checkpoint kinases do?

A

stabilise activate Wee1 kinase, repress Cdc25 phosphatase- leading to inhibition of Cyclin B/Cdk1

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71
Q

what are the G2/M checkpoint kinases?

A

ATM/ATR and Chk1/Chk2

72
Q

what does the spindle assembly checkpoint do?

A

prevents APC/C-Cdc20 activation until all chromosomes correctly attached to the mitotic spindle

73
Q

what activates the spindle assembly checkpoint?

A

if a kinetochore isn’t attached to a MT, if tension isn’t correct

74
Q

what does the mitotic checkpoint complex do?

A

binds and inhibits Cdc20 when kinetochores are not attached to MTs, and chromosome isn’t under tension

75
Q

what % of cancers are aneuploid?

A

90%

76
Q

what % of cancer mutations are caused by random mutations during replication?

A

66%

77
Q

what can high levels of cyclin E cause?

A

centrosome over-duplication

78
Q

what are reasons for increased segregation problems in women?

A

sister chromatids held together by cohesin, oocytes arrest in prophase I and may not be used for 20-25 years, older oocytes have less cohesin so less cohesion

79
Q

what does the drug ribociclib do?

A

inhibits CDK4 and CDK6

80
Q

what do DNA damage agents do? (type of chemotherapy)

A

inhibit DNA replication

81
Q

what do anti-metabolites do? (type of chemotherapy)

A

reduce metabolites- deplete dNTPs

82
Q

what do vinca alkaloids do? (type of chemotherapy)

A

inhibit microtubules so no chromosome segregation

83
Q

what do intercalating agents do? (type of chemotherapy)

A

inhibit replication by distorting DNA

84
Q

what do topoisomerase inhibitors do? (type of chemotherapy)

A

inhibit replication/segregation

85
Q

what do taxanes do? (type of chemotherapy)

A

inhibit MTs so prevent segregation

86
Q

what is the target of erlotnib?

A

EGFR, to block activation of Ras signalling, prevent G1-S transition

87
Q

what is the main form of programmed cell death?

A

apoptosis

88
Q
A
89
Q

how is development of fallopian tubes, uterus and upper vagina arrested in male foetuses?

A

anti-Mullerian hormone expressed to inhibited Mullerian duct development, Mullerian ducts then destroyed by apoptosis

89
Q

what is the difference between programmed cell death and necrosis?

A

necrosis is tissue wide not cell-specific, and is due to trauma not programmed

89
Q

how is the body plan sculpted by apoptosis?

A

in hand interdigital cells die by apoptosis, in tadpoles apoptosis in tail before they become frogs

89
Q

what does failure to induce apoptosis in the Mullerian duct in the male result in?

A

Persistent Mullerian duct syndrome causing hermaphroditism

89
Q

how does apoptosis resolve effects of drug treatments/heavy drinking on the liver?

A

these cause hyperplasia in liver which apoptosis resolves after drug clearance

90
Q

how is apoptosis involved in neural development?

A

neurons which don’t form connections with other neurons are eliminated by apoptosis

91
Q

how is apoptosis involved in immune cell development?

A

eliminates B and T cells which don’t recognise any foreign bodies or recognise self cells

92
Q

how is apoptosis involved in the immune response after an infection is destroyed?

A

apoptosis needed to reduced lymphocyte populations so only a few memory cells survive

93
Q

what does apoptosis result in?

A

phagocytosis of the dead cell by specialised phagocytes including macrophages and microglia, and non-professional phagocytes such as hepatocytes in the liver

94
Q

what is apoptosis mediated by?

A

proteases called caspases

95
Q

why are caspases called that?

A

cysteine aspartic acid proteases

96
Q

what are the 2 types of caspase?

A

initiator caspases and executor caspases

97
Q

what are the initiator caspases?

A

Caspase8 and Caspase9

98
Q

what are the executor caspases?

A

Caspase3 and Caspase7

99
Q

what happens in apoptosis? (overview)

A

cell shrinks, chromatin condenses, membrane starts blebbing, organelles disintegrate, loss of cell-cell contact, nucleus and organelles collapse, membrane blebbing continues, DNA digested, apoptotic bodies form, cell fragmentation, macrophages phagocytose apoptotic cell

100
Q

what is the critical amino acid in the active site of caspases?

A

Cys residue

101
Q

where do caspases cleave peptide sequences?

A

immediately after an aspartic acid

102
Q

how are inhibitor caspases activated?

A

by dimerisation and self-cleavage

103
Q

what is initiator caspase activation induced by?

A

the intrinsic or extrinsic pathway

104
Q

how are executioner caspases activated?

A

proteolytic cleavage of inhibitory domain by initiator caspases

105
Q

what ensures apoptosis induction is self-amplifying and irreversible?

A

1 initiator caspase initiates many executor caspases

106
Q

what 4 key features of apoptosis does caspase activation define?

A

normally inactivated, destructive, self-amplifying, irreversible

107
Q

how many cellular proteins do caspases cleave to ensure cell death?

A

over 2000

108
Q

how do caspases degrade DNA?

A

by destroying iCAD (inhibitors of Caspase-inactivated DNase), which activates CAD (cuts DNA)

109
Q

what does CAD do?

A

cuts DNA

110
Q

what outer membrane protein do caspases destroy?

A

Flippase

111
Q

what does Flippase do?

A

keeps phosphatidylserine (PS) on the inner membrane

112
Q

what does loss of Flippase due to destruction by caspase cause?

A

phosphatidylserine to move to the outer membrane- the ‘eat me signal’ for phagocytes

113
Q

what is the ‘eat me signal’ for phagocytes?

A

phosphatidylserine on the outer membrane

114
Q

what does destruction of cadherin by caspase lead to?

A

loss of cell adhesion

115
Q

what does destruction of actin by caspase lead to?

A

loss of cell shape

116
Q

what does destruction of lamin A by caspase lead to?

A

loss of nuclear membrane

117
Q

what does destruction of iCAD by caspase lead to?

A

digestion of DNA

118
Q

what does destruction of DNA repair enzymes (PARP) by caspase lead to?

A

no DNA repair

119
Q

what does destruction of MDM2 by caspase lead to?

A

activation of p53

120
Q

what does destruction of Flippase by caspase lead to?

A

phagocytosis due to PS exposure on outer membrane

121
Q

how do checkpoint kinases activate p53?

A

by inhibiting the interaction between p53 and an E3 ubiquitin ligase (Mdm2)

122
Q

what does Mdm2 do?

A

binds to and degrades p53

123
Q

what is PUMA?

A

p53 unregulated modulator of apoptosis

124
Q

why is hyperactive p53 lethal?

A

healthy cells are induced to arrest the cell cycle and commit apoptosis

125
Q

what does PUMA inhibit?

A

B-cell lymphoma 2

126
Q

what is BCL-2?

A

an oncogene that is overexpressed in approx. 45% of all cancers

127
Q

what does BCL-2 do?

A

binds to the outer mitochondrial membrane where it inhibits a pore-forming protein called BAX

128
Q

what is BAX?

A

BCL-2 associated protein X

129
Q

what does PUMA binding to Bcl-2 allow BAX to form?

A

a pore in the outer mitochondrial membrane with the initiator Caspase9

130
Q

what do BAX and Caspase9 form?

A

complex called the apoptosome

131
Q

what does the apoptosome do?

A

dimerises and activates Caspase9 triggering apoptosis

132
Q

what is Li-Fraumeni Syndrome?

A

patients inherit 1 mutant p53 gene and have a near 100% risk of developing cancer- as p53 blocks cell division and promotes apoptosis

133
Q

what is the action of Venetoclax?

A

inhibits BCL-2 resulting in activation of BAX and restoring the intrinsic apoptosis pathway to p53 mutant cancers

134
Q

how can apoptosis be induced extrinsically?

A

cell-to-cell contact between death receptors, and by cytokines

135
Q

what are cytokines?

A

small proteins released/expressed mostly by immune cells

136
Q

what is the TNF family?

A

tumour necrosis factor family- cytokines that mediate apoptosis through the extrinsic pathway

137
Q

what does TNF bind to?

A

the TNF receptor (TNFR) which is expressed on many cell types

138
Q

what is FAS ligand (FASL) a member of?

A

the TNF cytokine family

139
Q

what is the receptor for FASL?

A

FAS

140
Q

what is FAS expressed on?

A

immune cells such as macrophages

141
Q

what is the other name for the TNF family?

A

death receptors

142
Q

what are TNFR family proteins?

A

transmembrane domain proteins with a death domain on their cytoplasmic side

143
Q

what does binding of TNF to TNFR/FASL to FAS cause?

A

structural changes in the death domain which trigger the recruitment of multiple proteins including the inactive form of the initiator Caspase8 to form the DISC complex

144
Q

what is the DISC complex?

A

death induced signaling complex

145
Q

what does the DISC result in?

A

dimerisation and activation of Caspase8 which triggers activation of executor caspases and cell death

146
Q

what protein counteracts the effect of DISC activation?

A

FLIP protein (Flice inhibitory protein)

147
Q

how does FLIP work?

A

FLIP is very similar to the Caspase8 protein except it lacks any protease activity so it acts as a Caspase8 dummy in the DISC complex preventing Caspase8 from being activated

148
Q

when is FLIP important?

A

in protecting expanding mature lymphocyte populations from apoptosis

149
Q

what is excessive activation of TNF signaling associated with?

A

chronic inflammation, can lead to development of autoimmune and immune-mediated disorders including rheumatoid arthritis. ankylosing spondylitis, inflammatory bowel disease, refractory asthma

150
Q

how does constant TNF signaling induce chronic inflammation?

A

cell death in epithelia increasing penetration of pathogenic molecules and microbes, Caspase8 can induce expression of proinflammatory genes, TNFR signaling can invoke other modes of cell death such as necroptosis- these result in release of cellular contents- induces inflammation

151
Q

what % in people in the US suffer from arthritis and joint disease?

A

20%

152
Q

what is a TNF inhibitor drug that is a monoclonal antibody against TNF?

A

infliximab

153
Q

what is etanercept?

A

a TNFR-antibody fusion, drug that inhibits TNF

154
Q

what causes autoimmune lymphoproliferative syndrome (ALPS)?

A

mutations in the FAS gene

155
Q

what are the symptoms of ALPS?

A

chronic non-malignant lymphoproliferation, autoimmunity, cancers, lymphadenopathy, splenomegaly

156
Q

why do mutations in the FAS gene lead to ALPS?

A

due to failure to cause apoptosis in B and T cells

157
Q

what does adenovirus release a protein to inhibit?

A

p53

158
Q

what does HPV release a protein to promote?

A

p53 degradation

159
Q

how can enveloped viruses infect phagocytes?

A

coat themselves in phosphatidylserine to get phagocytes to envelop them

160
Q

how does HIV avoid immune detection?

A

upregulates FAS and TNF in T-cells resulting in T-cell death

161
Q

how does Trichomonas vaginalis utilise apoptosis?

A

induces apoptosis to allow it to invade the vaginal/urethral mucosa, induces apoptosis in immune cells such as macrophages to promote survival

162
Q

how do T cells utilise FASL to kill foreign/diseased cells?

A

FASL mediated interaction with the FAS death receptor on the target cell to induce apoptosis

163
Q

what are key immune checkpoint proteins expressed on T cells?

A

CTLA-4 and PD-1

164
Q

what is CTLA-4?

A

cytotoxic T-lymphocyte associated protein 4

165
Q

what does CTLA-4 bind to?

A

the B7 receptor

166
Q

what is PD-1?

A

programmed death protein 1

167
Q

what does PD-1 bind to?

A

PD-L1 (programmed death ligand 1)

168
Q

what is the function of CTLA-4?

A

regulates T-cell proliferation early in an immune response, primarily in lymph nodes

169
Q

what is the function of PD-1?

A

suppresses T cells later in an immune response, primarily in peripheral tissues

170
Q

what do CTL-4 mutant mice display?

A

aggressive early onset autoimmune disease

171
Q

what do PD-1 mutant mice suffer from?

A

late-onset autoimmune diseases like arthritis

172
Q

how do tumours avoid destruction by T cells?

A

upregulating immune checkpoint proteins (PD-L1 particularly)- by amplifying the locus of the PD-l1 gene, upregulation of PD-l1 expression due to loss of Rb/p53, oncogenic transcription of PD-L1 by Myc

173
Q
A

MIMS (15 decks)

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