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MCG > LEC50: Cell Cycle Progression and Checkpoints > Flashcards

LEC50: Cell Cycle Progression and Checkpoints Flashcards

1
Q

what determines entry into S phase?

A

phosphorylation of pRb

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2
Q

what are the 3 kinds of signaling/feedback in the cell cycle?

A

1) the previous cyclin-CDK is responsible for activating the next step
2) negative feedback, the next step turns off the previous step - if the 2nd complex is active, it causes phosphorylation and inhibition of the previous step
3) amplifying signal: previous complex starts the next complex to go, but there are steps that cause amplification fo that 2nd complex to cause a signal

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3
Q

what upregulates cyclin D?

A

Erk pathway:

Growth factors bind to cell surface receptor

Receptor is a RTK on the membrane

It auto-phoshporylates

Activates Ras

Ras > Raf

Raf > Mek

Mek > ERK

ERK upregulates Cyclin D

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4
Q

what do cells need to proliferate? why?

A

cells need growth factors b/c they need upregulation of cyclin D, and cyclin D is what causes proliferation

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5
Q

what does Rb mean

A

retinoblastoma

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6
Q

how is Rb normally? what does it do?

A

Rb normally bound to E2F

When Rb bound to E2F, Rb acts as a repressor, prevents E2F from functioning; E2F expression is **off **in Rb presence

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7
Q

what is E2F?

A

a transcription factor that regulates gene expression

turned OFF when Rb binds it

turns ON when Rb gets phosphorylated

E2F’s target = Cyclin E

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8
Q

what disrupts Rb-E2F complex? resulting cascade?

A

Cyclin D-Cdk4 and Cyclin D-Cdk6 phosphorylate Rb

this releases Rb from E2F

E2F can now act as a transcription factor; regulates Cyclin E

Cyclin E levels increase from E2F transcription activation

Cyclin E-Cdk2 become active; Rb is further phosphoryalted as Cyclin E-Cdk2’s substarte; and E2F is totally released

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9
Q

what are the 2 kinds of E2F targets

A

1) high affinity target: low levels of E2F will turn it on
2) low affinity targets: dihydrofolate reductase, thymidylate synthase, DNA pol-Alpha

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10
Q

describe signal cascade of pRb, E2F, leading into S phase?

A

Rb bound to E2F means no gene expression that’s E2F dependent occurs

Growth factors upregulate Cyclin D

Cyclin D-Cdk4 or 6, active now, phoshporylates Rb enough that E2F turns on Cyclin E

Activated Cyciln E-Cdk2 phosphorylates Rb further

E2F now fully active

Now can enter into S phase

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11
Q

what regulates Cyclin A gene expression?

A

E2F

Cyclin A is a low affinity E2F target; so Cyclin A is only turned on when E2F is fully free of Rb

THEN Cyclin A is upregulated, and Cyclin A-Cdk2 can initiate origin firing for DNA synthesis

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12
Q

what triggers DNA synthesis?

A

Cdk phosphorylation

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13
Q

what are the stipulations for origin firing?

A

1) origin must fire for DNA synthesis to occur
2) EACH origin must fire ONLY ONCE to get a 2N to 4N DNA synthesis

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14
Q

what assembles to initiate DNA replication? when?

A

pre-replication compres (pre-RC)

occurs during G1

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15
Q

what activates polymerase to do DNA replication/start origin firing?

A

Cyclin E-Cdk2 and Cyclin A-Cdk2 phosphorylate polymerase

polymerase is then active

ONLY CAN OCCUR when the poylmrease is sitting ON THE ORIGIN - it is a** localized ability, **kinase is localized to the origin, polymerase gets phosphorylated and fires

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16
Q

what ensures initiation of replication occurs only 1x each round?

A

Cdk phosphorylation of proteins involved in DNA replication includes licensing factors which ensure initiation occurs only 1x each round

factors then are degraded

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17
Q

what are the dual effects of phosphorylation at the origin of replication?

A

1) phosphorylation fires the origin
2) phosphrylation removes the marks of an origin that’s ready to be fired- ensures firing doesn’t occur again once it already has

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18
Q

what mediates entry from G2 to M?

A

Cyclin B/Cdk1 phosphorylation

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19
Q

what is stimulated by mitotic Cdk-cyclin activation?

A

1) nuclear envelope breakdown
2) chromosome condensation
3) mitotic spindle formation
4) targeted protein degredation

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20
Q

what causes nuclear membrane to break down?

A

Loss of a pressor means Cyclin B levels increase, due to transcriptional upregulation

Cdc25 becomes phoshprylated in response to completion of DNA synthesis

this activates Cyclin B/Cdk1

a component of the nuclear membrane is a substrate for Cyclin B/Cdk1; when phosphorylated, Lamins A and C break down, thus nuclear membrane breaks down

21
Q

what makes up nuclear membrane?

A

lamins, which polymerize w/ each other

22
Q

is nuclear envelope breakdown reversible? how?

A

yes

When Cyclin B/Cdk1 activity decreases, phosphorylation of Lamins is reversed by a nonspecific phosphatase which removes a phosphate from Lamin, and Nuclear membrane spontaneously will reform

23
Q

what is condensin?

A

protein that mediates condenstion of DNA into chromsome

when ACTIVE, mediates condensation of DNA into chromsomes

24
Q

when / why does chromoatin condensation occur?

A

condensin condensation of DNA occurs as a subsrate of Cdk1/Cyclin B complex, like nuclear membrane breakdown

when nuclear membrane breaksdown due to phosphorylation of Lamins by Cdk1/Cyclin B, Condensins come together and chromatin condensation occurs

25
Q

how does sister chromatid separation occur? when?

A

anaphase of mitosis

Cohesin holds sister chromatids together

Separase, enzyme, is bound to an inhibitor, Securin, is Inactive

when the APC is active, it Ubiquitinates Securin, making Separase active

Separase thus cleaves Cohesin, and sister chromatids can separate

26
Q

how does APC become activated?

A

b/c it’s associated w/ a co-factor, either Cdc20 or Cdh1

when activated, Ubiquitinates and degrades Securin; this results in Separase activation

thus Sister chromatids Separate

27
Q

what are APC’s dual functions?

A

APC responsible for sister chromatid separation

AND

active in degredation of Cyclin B, which is necessary for exit from Mitosis

28
Q

G1:

Kinase?

Cyclin?

Mechanism of upregulating cyclin transcriptionally?

Substrate of the kinase?

Effect of phosphorylation?

A
29
Q

G1-S:

Kinase?

Cyclin?

Mechanism of upregulating cyclin transcriptionally?

Substrate of the kinase?

Effect of that phoshporylation?

A
30
Q

S phase:

Kinase?

Cyclin?

Mechanism of upregulating cyclin txnly?

Substrate of the kinase?

Effect of that phosphorylation?

A
31
Q

what causes mitotic exit?

what events occur as result?

A

Cyclin B degradation -> Mitotic exit

Chromosomes decondense, nuclear membrane reforms

32
Q

checkpoint?

A

an ordered series of events dependent on completion of a previous step

senses a problem, causes cell cycle to stop

33
Q

why doesn’t cyclin de-upregulation exist?

A

because checkpoints do exist

34
Q

what is restriction point?

A

mediated by pRb phoshporylation in response to growth factors

lack of growth factors causes cell to arrest in early G1 at this restriction point

provides connection btwn extracellular signaling & cell cycle control

after restriction pt, cell is committed to DNA replication

35
Q

what does loss of checkpoint control cause?

A

uncontrolled proliferation aka cancer

36
Q

how does growth factor signaling contribute to proper cell cycle vs cancerous?

A

growth factor signaling results in transcriptional upregulation of cyclin D

this triggers phosphorylation of pRb and release of E2F

this regulation is lost in cancer

37
Q

what does DNA damage activate?

A

2 checkpoints: G1-S and entry into M

38
Q

purpose of each DNA damage checkpt?

A
  1. prior to S phase, so cell doesn’t replicate w/ damage
  2. prior to M phase, so cell doesn’t undergo cell division w/ damaged chromosomes
39
Q

describe the normal state of the G1 checkpoint

A

normally, the tumor suppressor p53 binds to Mdm2, a ubiquitin ligase that polyubiquitinates p53 and keeps p53 low in absence of DNA damage

40
Q

in presence of DNA damage, describe activation of G1 checkpoint

A

kinase cascade is triggered, Mdm2 and p53 become modified

p53 also is acetylated

this disrupts Mdm2-p53 interaction, p53 is no longer ubiquitinated

p53 levels increase; p53 binds to DNA and turns on gene expression, mainly via p21, the CIP inhibitor

thus CELL CYCLE ARRESTS b/c p21 binds to Cyclin E/Cdk2 and prevents entry into S phase

41
Q

what are p53’s effects in regulating cell cycle

A

cell cycle arrest and apoptosis, depending on if damage is great in cell (apoptosis) or reparable (cycle arrest)

42
Q

if DNA damage is present, what prevents entry into Mitosis?

A

DNA damage here triggers kinase cascade resulting in inhibitory phoshprylation of Cdc25

thus, no activation of Cyclin B/Cdk1 occurs

43
Q

how does unreplicated DNA prevent entry into mitosis?

A

Cdc25 must be phosphorylated to be active

this phosphorylation doesn’t occur until DNA synthesis is complete, and full 4N DNA is achieved

44
Q

what is spindle checkpoint function?

A

arrests cells in mitosis until all chromosomes are properly aligned in metaphase

45
Q

when spindle checkpoint is OFF, what happens?

A

APC is active; it ubiquitinates securin

this means separase is active

cohesin is cleaved

sister chromatids are separated

46
Q

when spindle checkpoint is ON, what happens?

what causes this?

A

APC is inactive

do not get separation of sister chromatids

APC inactivity maintained if there’s a microtubule attached to every kinetochore; if each kinetochore has a MT, they align the sister chromatid, and those MTs are responsible for pulling the sister chromatid apart

so an unoccupied kinetochore, unbouned by a MT, can send a signal to APC to inhibit it

47
Q

what determines APC activity in the spindle checkpoint?

A

kinetochore occupany

if there isn’t a MT at any kinetochore, then APC activation is DELAYED so checkpoint is ON

48
Q

how could spindle checkpoint be exploited therapeutically

A

a MT disrupting agent will prevent a cell from dividing b/c it depolymerizes all of the MT in a cell, as if any MT are depolymerized, and even 1 kinetochore unoccupied, you trigger the spindle checkpoint and cause same cellular response as you would by depolymerizing all of the MTs

49
Q

how can chemotherapeutic drugs use cell cycle to their advantage?

A

if disrupte cell cycle by disrupting DNA damage or disrupting spindle formation, or have any DNA breaks, then cell will arrest at a checkpoint

MCG (77 decks)

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