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translational > Eukaryotic cell cycle (wk3) > Flashcards

Eukaryotic cell cycle (wk3) Flashcards

1
Q

List the phases in the eukaryotic cell cycle (mitosis)

A 
G1 phase 
S phase
G2 phase
M phase 
- prophase
- metaphase
-anaphase
- telephase
- cytokinesis 
G0 phase
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2
Q

What happens in the G1 phase? (mitosis)

A

Interphase: growth & preparation for DNA synthesis

  • chromatin fibres become less coiled & more active for transcription
  • synthesis of RNAs
  • longest phase
  • stays here until growth signal received or restriction (mitogen)
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3
Q

What happens in the S phase? (mitosis)

A

Interphase: DNA replication

  • DNA & histone synthesis
  • chromosomes doubled
  • sister chromatids are firmly attached to centromeric region
  • pair of centrioles (at right angles) are associated with a centrosome & this is duplicated
  • the centrosome-centriole gives rise to the mitotic spindle
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4
Q

Where are centrioles absent?

A

in plants & most fungi

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5
Q

What happens in the G2 phase? (mitosis)

A

Interphase

  • contains 2 chromatids
  • organelle duplicated
  • cytoskeleton dismantled to provide resources for the mitotic phase
  • production proteins for M phases
  • double protein mass
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6
Q

What happens in prophase? (mitosis)

A

in the nucleus
1. chromosomes condense (condensin complex)

  1. kinetochore complexes bind to centromeres
  2. centrosomes move to opposite poles
  3. centrioles build long polymers of tubulin = mitotic spindle

Prometaphse:

  1. nuclear envelope starts to break
  2. chromosomes captured, bi-orientated & brought to the spindle equator
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7
Q

What happens in metaphase? (mitosis)

A
  1. nuclear envelope disintegrates
  2. spindle microtubules from each pole attach to chromosome kinetochores
  3. kinetochore-microtubules exert tension on chromatids
  4. chromosomes align on spindle equator (the metaphase plate)
  • dynamic assembly-disassembly of microtubules search & capture chromosomes & align along metaphase plate
  • sensing mechanisms correct inappropriate kinetochore attachements

***metaphase/anaphase checkpoint

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8
Q

What is the G0 phase?

mitosis

A

= Quiescent
= after completion of mitosis do not enter the G1 phase to begin the cycle again

= inactive

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9
Q

What happens in anaphase? (mitosis)

A
  1. sister chromatids seperate
  2. cleavage of cohesin initiates metaphase-anaphase transition
  3. attached chromatids move to each pole
  4. poles themselves move further apart (late anaphase)
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10
Q

What happens in telephase? (mitosis)

A
  1. nuclear envelope reforms
  2. chromatids de-condense
  3. mitotic spindle breaks down
  4. exit from mitosis
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11
Q

what happens in cytokinesis? (mitosis)

A
  1. contractile ring forms around cell perimeter (actin & myosin)
  2. pulls the plasma membrane inward
  3. cell separates into two daughter cells

= cell division

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12
Q

3 types of microtubules in the mitotic spindle

A
  1. astral microtubules = cell anchoring
  2. kinetochore microtubules = kinetochore attachment
  3. interpolar microtubules = extension & contraction
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13
Q

metaphase/anaphase checkpoint = APC/C = spindle checkpoint = M checkpoint

if activated?

A

= are all chromosomes/kinetochores attached correctly to the mitotic spindle

  • sister chromatids must be stably bi-orientated on mitotic spindle
  • dynamic assembly-disassembly of microtubules search & capture chromosomes & align along metaphase plate
  • sensing mechanisms correct inappropriate kinetochore attachements
  1. if activated sets off a cascade that results in cohesin cleavage & sister chromatid release
  2. M phase cyline (end of mitosis/exit from cell cycle)
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14
Q

G2/M checkpoint

A

DNA damage/integrity?
All DNA replicated?
cell size?

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15
Q

G1/S checkpoint

A
  • is the environment favourable –> mitogens, nutrients
  • is there DNA damage?
  • cell size?
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16
Q

G1 start site (mitosis) is stimulated by

A

mitogens = stimulate irreversible entry into cell cycle

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17
Q

mitogen & 3 examples

A

chemical substance that triggers a cell to start the cell cycle e.g., certain growth hormones, cytokines, hormones

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18
Q

what do mitogens trigger

A

cyclin D gene transcription

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19
Q

what is cyclin D required for

A

passing the restriction point in mitosis

  • provide substrate specificity & switch for activation of CDK
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20
Q

what does cyclin D bind to

A

CDK = cyclin-dependent kinase = promotes or inhibits downstream events

  • initiates phosphorylation
  • phosphatase turns off
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21
Q

what is CDK

A

cyclin-dependent kinase = protein kinase activity

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22
Q

what does protein kinase do

A

catalyse the transfer of phosphate groups = adds a phosphate group = turns activity on

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23
Q

what does phosphatase do

A

catalyse the removal of phosphate group

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24
Q 
what are the cyclin families associated for each phase?
G1
G1-S
S-G2
M
A

Cyclin D, CDK4, CDK6
Cyclin E, CDK2
Cyclin A, CDK2, CDK1
Cyclin B, CDK1

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25
Q

What is the function of the cyclin - CDK complexes

A

= each phosphorylates a key set of target proteins

  • trigger production/activation of key proteins for following phase e.g., centrosome duplication, helicase or polymerase activity, nuclear envelope breakdown
  • trigger production/activation of the next set of CDK-cyclins
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26
Q

do CDK protein levels remain constant throughout the cell cycle?

A

yes but inactivated unless bind to cyclins

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27
Q

What regulates CDK activity?

A

1) cyclin expression
2) phosphorylation/dephosphorylation
3) CKIs (CDK inhibitors) expression
4) Cyclin & CKI degradation

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28
Q

steps in cyclin D expression

A
  1. mitogenic factors (growth factors/cytokines e.g., EGF)
  2. receptor tyrosine kinase
  3. signalling cascade (e.g., Ras/Raf/MAPK)
  4. transcription factor activation (e.g., Myc, AP-1 (Jun/Fos))
  5. cyclin D expression = start cell cycle
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29
Q

Cyclin D’s role in entry to S phase

A
  • normally Rb sits in the cell binded to E2F
  • Cyclin D1 causes phosphorylation on Rb sites
  • Phosphorylation on Rb sites unbind it from E2F
  • allows E2F to bind to promoters of various genes which it then is involved in transcription of S phase genes
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30
Q

what is Rb protein?

A

retinoblastoma protein “the gatekeeper”

31
Q

what is E2F?

A

transcription factor required for S phase genes e.g., cyclin E

32
Q

what inhibits E2F

A

de-phosphorylated Rb

33
Q

Cyclin E required for initiation of…

A

DNA replication

  • E2F expresses Cyclin E
  • activates Cyclin E-CDK2
  • causing hyperphosphorylation of Rb
  • activate DNA replication proteins such as helicase
34
Q

role of CAK

A

= CAK complex adds activating phosphate group to the CDK-cyclin complex
- abundant, not-regulated

35
Q

role of Wee1 in phosphotase

A

= inhibiting kinase that phosphorylates CDKs (eg CDK2/1) and inhibits their activity

36
Q

role of Cdc25 in phosphatase

A

= activating phosphatase = removes the inhibitory phosphate = re-establishes CDK activity

37
Q

overall role of Wee1 & Cdc25

A

= integrate upstream signals at G1 & G2 checkpoints e.g., DNA damage
= control CDK-cyclin activity (pause cycle) without degrading cyclin = rapid

  • positve & neg feedback loops
38
Q

role of CKIs

A

= cyclin-dependent kinase inhibitor

  • bind to CDK-cyclin complex & inactivate (mask active site)
  • or can bind CDK monomer & stop its interaction with the cyclin

= inhibit the action until needed for new cycle

39
Q

What are the two major families of CKIs

A
  • inhibitors of Kinase 4 (INK4s) = react with cyclin D-CDK complexes in G1/S transition
  • Cdk inhibitory proteins (CIPs) = react with Cyclin D, E, A, B complexes
40
Q

what is the point of targeted cyclin destruction & how does it occur

A
  • coordinated cyclin destruction allows cell cycle progression in forward direction
  • occurs via the ubiquitin proteasome system
41
Q

ubiquitination of cyclin by ubiquitin ligases steps

A
  1. ubiquitin is added to the cyclin
  2. cyclin is then recognised by the protostome which targets it for destruction
  3. cyclin is destroyed
  4. CDK inactivates
42
Q

General process of ubiquitination & proteasomal degradation

A
  1. E1 (activating enzyme) passes the ubiquitin to a conjugating enzyme (E2)
  2. E2 conjugates it to ubiquitin ligase
  3. the complex interacts with the substrate, allowing the transfer of ubiquitin
  4. the tag protein on the substrate is recognised by proteasome & degraded
  5. ubiquitins released & recycled & broken down protein released
43
Q

what are the cell cycle E3 Ubiquitin ligases

A

SCF & APC/C

44
Q

SCF complex role

A

= SKP1, Cullin1, F-box containing complex

  • primarily G1 to S phase, cyclin D & E destruction, CKIs destruction
45
Q

APC/C role

A

= anaphase-promoting complex/cyclosome

  • cyclin A & B destruction
  • onset & exit of mitosis & reset whole system as enters back into G1
46
Q

Ubiquitin ligases

A
  • variable targets at variable stages of the cycle
  • ->depend on subunits in complex
  • ->depend on phosphorylation of target proteins (which can alter recognition by ubiquitin ligases)
47
Q

role of F-box proteins

A

= contained in the SCF complex

  • confers substrate recognition –> ubiquitinate different protein targets - cell cycle dependent
48
Q

TGF-Beta

A
  • can work as a mitogen & an anti-mitogen
49
Q

example of anti-mitogen pathway in prevention of G1/S transition

A
  1. TGF-B stimulates phosphorylation which causes the binding of Smad4 2. the Smad4 transcription factor increases the production of Ink4 cytokine inhibitors
  2. the Ink4 (CKI) inhibits binding of cyclin D to CDK and inhibits G1/S transition
50
Q

role of P53 protein - DNA damage response (DDR) activates G1/S & G2/M checkpoints

A

= transcription factor that can regulate many genes involved in cell cycle

  • repair in response to damage or if not
  • trigger apoptosis
51
Q

what happens if the chromosomes are not attached correctly to the mitotic spindle?

A

aneuploidy = odd number of chromosomes = affect on genetic stability

52
Q

what protein complex controls the metaphase to anaphase transition & sister chromatid seperation?

A

APC/Cdc20

  • tags proteins for degradation that lead to the cleavage of COHESIN COMPLEX (holds the chromatids together)
  • it binds to the enzyme (securin) which is otherwise stopping the seperation of cohesin
  • then anaphase
53
Q

How does the Kinetochore attachment control complex work in chromatid seperation?

A
  • when the kinetochores are unattached, CDC20 is sequestered
  • once the kinetochores are attached, CDC20 proteins are released allowing it to release the APC/C creating a APC/CDC20 complex
  • APC/C triggers degradation of securin
  • loss of securin activates separase
  • separase cleaves cohesin
  • loss of cohesin
  • chromatid seperation
54
Q

what does APC/CDH1 control?

A
  • cyclin A & B degredation
  • exit from mitosis
    enter G1 with no cyclins, wait for new signal
55
Q

How does the cell progress through various stages of the cell cycle?

A

Controlled expression and degradation of various cyclin proteins

EXPLANATION
- Cells progress through the cell cycle by controlled expression and degradation of cyclin proteins. Cyclin-dependent kinases (CDKs) are always present in the cell and are not degraded after progression to a new stage of the cell cycle. Cyclins bind their respective CDKs to activate them. This activation causes a chain of events that allow the cell to progress to the next phase of the cell cycle. Afterwards, cyclins are ubiquinated and degraded until they are needed again

56
Q

SAQ: What stimulus is required for quiescent cells to re-enter the cell cycle? What events occur after stimulation?

A

Quiescent (G0) cells re-enter the cell cycle after stimulation by growth factors. Growth factors act as mitogens stimulate signalling cascades (such as MAPK) that activate transcription of cyclin D, the first cyclin in the cycle that is essential for G1-S progression. In particular, expression of cyclin D is required for cyclin D-CDK4/6 phosphorylation of Rb, which leads to inactivation of Rb as a repressor of E2F. E2F is the transcription factor required for expression of S phase genes, including the S phase cyclins E and A.

57
Q

Order the cell type in terms of division rate from highest to lowest:

  • mature neurons
  • skin cells
  • liver cells
A
  1. Skin cells - high, 30 days
  2. Liver cells - Low, 1-2 divisions/yr
  3. mature neurons - terminal differentiation, 1
58
Q

What causes cell cycle dysregulation & disease?

A
  1. chronic mitogenic stimulation (injury or inflammation)

2. mutation - germ-line or somatic

59
Q

example of mitogenic stimulation: atherosclerosis

A

= build up of fatty (cholesterol) plaques in the blood vessel wall causes chronic inflammation

hypercholesterolemia –> cholesterol enters vessel wall –> stimulate immune cell infiltration –> macrophages get stuck –> chronic production of growth factors & inflammatory cytokines (mitogens) –> mitogens stimulate vascular smooth muscle cells (VSMC) in wall –> VSMC de-differentiation or phenotypic switch –> lose contractile phenotype, gain proliferative phenotype, migrate into intimal space (intimal hyperplasia) –> vessel wall remodels inwardly due to accumulation (atheroma) –> eventually blocks vessel (stenosis) and restricts blood flow or ruptures leading to clot (stroke or heart attack)

60
Q

example of mitogenic stimulation: vascular restenosis

A

stent implantation or balloon angioplasty used to remove atheroma –> restore blood flow –> BUT - stent/balloon cause mechanical injury to wall –> endothelial cell damage (loss of nitric oxide, thrombus, inflammation & mitogen production) –> neointimal hyperplasia (SMC de-differentiation + profliferation) –> inward remodelling (re-stenosis)

61
Q

how is re-stenosis avoided?

A
  • by the use of drug-eluting stents

e. g.,
- paclitaxel = inhibits tubulin/spindle formation
- sirolimus (rapamycin) - signalling pathways, CKI induction

62
Q

what is hyperplasia?

A
  • chronic stimulation (
    increase proliferation & decrease apoptosis)
  • increase cell numbers & tissue growing
63
Q

what is neoplasia?

A
  • stimulus is not required (possibly a result of a mutation/genetic/epigenetic change)
  • grow & divide in the absence of mitogenic signals or presence of antimitogenic signals
  • ability to evade checkpoint activation, senescence, cell death
64
Q

what are tumour suppressors?

A
  • genes that normally block cell cycle progression
  • prevent the formation of cancerous tumours when they are working correctly e.g., the cell cycle proteins involved in checkpoint control
65
Q

mutations in tumour suppressors

A
  • cause loss of function = uncontrolled cell proliferation

- typically recessive

66
Q

what ist he Knudson two-hit hypothesis (1971)

A
  • since both alleles of a tumour suppressor gene must be lost for cancer formation, two “hits” are required

THEREFORE, there is an increased cancer risk with inherited germline mutations
- only one other somatic mutation in the functional allele of the gene is necessary for cancer formation

67
Q

role of proto-oncogenes

A

= genes that normally stimulate cell cycle progression

e.g., cyclins, CDKs, Cdc25

68
Q

what are oncogenes?

A

= mutated proto-oncogenes

  • overexpression (e.g. gene amplification, translocation, reduced proteolysis)
  • gain-of-function mutations (constitutively expressed & active, molecular switch, upstream signals of activation or inhibition no longer required)
  • dominant mutations (only need one allele)
69
Q

can F-box proteins be suppressors or oncogenes?

A
  • they can have an onocogenic suppressor action depending on the role of the specific targets they tag for proteolysis & degradation, & the cellular context
70
Q

can APC/C subunits be suppressors or oncogenes?

A

yes

71
Q

how is the cell cycle different in terminally differentiated cells?

A
  • aberrant cell cycle entry is connected to cell death
72
Q

example of terminally differentiated cells..

A

Mature neurons

  • maintained in a G0 state, no longer cycle
  • neurons need to withdraw from the cell cycle so they don’t loose dendrites for example
73
Q

role of cell cycle in neurodegeneration

A
  • re-entry into the cell cycle causes cell death
  • cell cycle abnormalities evident in early stages of neurodegenerative diseases e.g. Alzheimer’s, Parkinson’s, ALS/MND
  • but we don’t know the cause or stimuli

translational (2 decks)

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