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Cell Biology (BY1CB1) > Week 8(Cell Cycle Activities of CDKs and the Ubiquitin Ligases) > Flashcards

Week 8(Cell Cycle Activities of CDKs and the Ubiquitin Ligases) Flashcards

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1
Q

When do G1/S cycling accumulate?

A

During G1

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2
Q

What is Retinoblastoma (Rb)?

A

A pocket protein that sequesters (holds out of action) members of the E2F family of transcription factors.

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3
Q

What do G1/S CDK do?

A

phosphorylates Retinoblastoma (Rb)

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4
Q

What does E2F stimulate?

A

stimulates the transcription of genes that promote entry into S-phase such as G1-cyclins, S-cyclins and DHFR (dihydrofolate reductase).

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5
Q

What is Phosphorylating Rb part of?

A

a Feedback Loop which Promotes Entry into S phase

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6
Q

Why might we want to prevent entry into S-phase?

A

The arrest of the cell cycle in G1 or G2
following DNA damage reduces the risk that
a neoplastic change will be passed onto the
daughter cells.

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7
Q

What can cause DNA damage?

A

DNA damage includes damage done by
ultraviolet and x-irradiation, and
chemotherapeutic drugs.

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8
Q

How does the DNA damage checkpoint work?

A

Severe DNA damage in G1 increases the activity
of p53.

p53 is a transcription factor.

In undamaged cells, p53 is unstable and is present
at low concentrations since it is bound by Mdm2,
a ubiquitin ligase that targets p53 for degradation.

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9
Q

What does DNA damage activate?

A

DNA damage activates kinases (ATM/ATR and
Chk1/Chk2) that phosphorylate p53,
releasing it from Mdm2.

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10
Q

p53 transcribes CKIs

A

Once stable and active, p53 turns on the expression of genes that encode CKIs (inhibitors of Cdk-cyclin complexes) such as p21 (p21 is similar to p27, a CKI normally present in early G1).

When p21 or p27 is bound to G1/S-Cdk or S-Cdk the complex is inactive.

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11
Q

What is Mdm2?

A

A ubiquitin ligase

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12
Q

describe the pathway from DNA Damage to Cell Cycle Arrest

A

DNA Damage

Stable p53

Transcription of p21 mRNA

p21 protein inhibits CDK-cyclin

Rb is unphosphorylated

No Free E2F

No entry into S phas

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13
Q

How is M-CDK activated?

A

-M-cyclins accumulate during G2.

-By the end of G2, the concentration of M-Cdk is high,
but the complex is inactive due to inhibitory phosphates
added by Wee1.

-Cdc25 removes the inhibitory phosphates.

-Cdc25 is activated by Polo kinase and by M-Cdk itself,
generating a positive feedback loop (M-Cdk also inhibits
Wee1).

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14
Q

Is M-CDK Is Activated by Positive Feedback?

A

Yes

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15
Q

What does M-Cdk do?

A

-Assembly of the mitotic spindle—
phosphorylates proteins that regulate
microtubule behaviour
-Chromosome condensation—phosphorylates the
condensin complex
-Nuclear envelope breakdown—phosphorylates
lamins
-Rearrangement of actin cytoskeleton and Golgi
-(Other kinases are also important).

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16
Q

DNA Replication Checkpoint Prior to Mitosis

A

Unreplicated DNA or unfinished replication forks send
a negative signal to block M-Cdk activation to
prevent mitosis.

The final target of the negative signal is Cdc25. As long
as cdc25 is inhibited, M-CDK will be inactive.

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17
Q

What is APC?

A

A ubiquitin ligase

18
Q

When is APC active?

A

APC is active when bound to the activating subunit Cdc20.

19
Q

What does the phosphorylation of APC by M-Cdk promote?

A

Cdc20 binding

20
Q

Is there a delay between M-Cdk activation and Cdc20-APC activation?

A

No

21
Q

What does Cdc20-APC targets securin for?

A

Degradation

Adds ubiquitin to securin

22
Q

What does Securin bind and inhibit?

A

separase (a protease)

23
Q

What happens after separase is free from securase?

A

separase cleaves the cohesin complex that holds the sister chromatids together

24
Q

Entrance to Anaphase=

A

Activation of Separase

25
Q

Describe the Spindle-Attachment Checkpoint that inhibits Anaphase

A

Free kinetechores block progression to anaphase
(a kinetechore is a specialised region of the chromosome that attaches to the microtubules of the spindle). Mad2 binds free kinetechores. The presence of Mad2 inhibits Cdc-20-APC So anaphase doesn’t take place
(Note this checkpoint works on a ubiquitin ligase
instead of a CDK).

26
Q

What is the function of Mad2?

A

Mad2 binds to unattached kinetochores and sends a negative signal to Cdc20-APC to inhibit it

27
Q

In response to DNA damage, what does S-Cdk promote?

A

DNA replication

28
Q

What does p53 indirectly inhibit?

A

G1/S CDK

29
Q

How does M-Cdk promote mitosis?

A

In response to unreplicated DNA, cdc25 is inhibited and so fails to activate M-CDK. In response to small size, wee1 inhibits M-CDK.o

30
Q

What does APC-cdc20 promote?

A

anaphase

-In response to free kinetechores, Mad2 inhibits APC-cdc20.

31
Q

What are mitogens?

A

Typically growth factors that stimulate cells to divide

32
Q

Explain how phosphorylation retinoblastoma is part of a feedback loop that promotes entry into S phase?

A
  1. A mitogen (growth factors that stimulates cells to divide) binds to tyrosine kinase receptors and cause a MAP kinase cascade
  2. MAP kinase phosphorylates transcription factors (activates them) so they can start transcribe immediate early genes
  3. One of those immediate early genes is a transcription factor called MYC
  4. MYC promotes the transcription of cyclins
  5. Retinoblastoma bound to E2F protein then an active CDK cyclin phosphorylates retinoblastoma causing it to release E2F
  6. E2F can start transcribing genes and in a positive feedback loop, more E2F is produced
  7. Eventually S-CDK is activated and DNA synthesis occurs
33
Q

What happens to G1/S-Cdk or S-Cdk when p21 or p27 is bound?

A

The complex is inactive

34
Q

What happens in the p53 pathway to prevent entry into S phase?

A
  1. DNA is damaged (e.g. by x-rays)
  2. ATM/ATR kinases are activated which activate CH1/CH2
  3. The kinases phosphorylate P3 thus releasing it from MDm2
  4. P53 levels rise
  5. P53 causes the transcription of P21/P27
  6. The mRNA is translated to produce the P21/P27protein which is a cyclin dependent kinase inhibitor protein
  7. This protein inactivates the G1/S-CDK
  8. Rb is unphosphorylated so remains bound to E2F
  9. No entry into S phase
35
Q

What is the function of Cdc25?

A

It removes inhibitory phosphates

36
Q

What activates Cdc25?

A

Cdc25 is activated by Polo kinase and by M-Cdk itself,
generating a positive feedback loop (M-Cdk also inhibits
Wee1).

37
Q

Explain what happens in the M-CDK activation pathway?

A
  1. CDK binds to a cyclin but is inactive
  2. CDK activating kinases adds phosphate to T loop
  3. Wee1 adds the inhibitory phosphate
  4. Cdc25 removes the extra phosphate
  5. Now the M-CDK is active
  6. Positive feedback encourages the phosphorylation of CDC 25 making more of it active which leads to a rise in M-CDK activity and an inhibitory effect on wee1
38
Q

What does target mean in this context?

A

Adds ubiquitin ligase to a substrate

39
Q

Explain the pathway that promotes entrance into anaphase?

A
  1. An inactive APC is phosphorylated by M-CDK and that allows Cdc-20 to bind and activate APC
  2. The APC-Cdc20 complex (ubiquitin ligase) adds ubiquitin to sequin which is then degraded in the proteasome
  3. Separase, once inactive (bound to securin) is now active
  4. Separase ‘chops up’ the cohesion’s between sister chromatids thus making it possible for the chromatids to be pulled apart in anaphase
40
Q

What is a kinetochore?

A

a kinetechore is a specialised region of the chromosome that attaches to the microtubules of the spindle

Cell Biology (BY1CB1) (16 decks)

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