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BS3003 > 7th Feb - Mitotic Spindle Assembly Checkpoint > Flashcards

7th Feb - Mitotic Spindle Assembly Checkpoint Flashcards

1
Q

What are the cyclin/cdk complexes required for progression from metaphase to anaphase?

A

Cyclin A- CDK1

Cyclin B- CDK1

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2
Q

What are the kinases that regulate mitotic entry?

A 
Plk1
Mps1 
BubR1
Cdk1
Haspin
NIMA-related kinases
Auora B
Aurora A
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3
Q

What is the function of Plk1?

A

Required for centrosome function, activation of Cdc25, cohesion phosphorylation, APC/C activation and cytokinesis

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4
Q

What is the function of Aurora A kinase?

A

Required for mitotic entry and spindle assembly

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5
Q

What is the function of Aurora B kinase?

A

Required for chromatin condensation and correction of improper MT-kinetochore attachments and mitotic exit

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6
Q

What is the function of NIMA-related Kinases?

A

Required for structural aspects of mitotic entry, centrosome function and spindle assembly

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7
Q

What is the function of Haspin?

A

Required for recruitment of Aurora B to chromatin

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8
Q

Outline the mechanism of Cdk1 activation

A

Aurora A –> Plk-1 –> Activates Cdc25 –> Cdk1 activation

POSITIVE FEEDBACK - Cdk1 phosphorylates Cdc25, activating it

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9
Q

Where does Cdk1 activation first occur?

A

At the centrosome which acts as a solid-phase signaling platform, thus increases speed and efficiency of signalling

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10
Q

Outline how mitotic entry is biochemically controlled

A
  1. Synthesis of cyclins A and B generates inactive Cdk1-cyclin complexes
  2. Cdk1 phosphorylated on T161 by CAK
  3. AuroraA activates Plk1 which phosphorylates Cdc25
  4. Cdc25 dephosphorylates T14/Y15 and partially activates Cdk1
  5. Partially activated Cdk1 further phosphorylates Cdc25, which further activates Cdk1
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11
Q

How is Cdk1 inhibited?

A

By phosphorylation on T14 and Y15 by Wee1

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12
Q

What are the two main criteria that must be filled before anaphase?

A

Full attachment of all chromosomes

Cdk1 must be switched off

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13
Q

Which two proteins must be destroyed before metaphase to anaphase transition?

A

Cyclin B

Securin

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14
Q

What is the evidence that cyclin B is destroyed before anaphase?

A

Mutant non-degradable cyclin B blocks mitotic exit
When Cdk1 is switched off cells revert to interphase state as competing phosphatases remove all the phosphates added by Cdk1

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15
Q

What is the evidence that securin is destroyed before anaphase?

A

Non-degradable securin prevents sister chromatid seperation

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16
Q

How is securin degraded?

A

By the cysteine protease seperase

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17
Q

How are both securin and cyclin B destroyed?

A

Targeted for proteasome destruction through the anaphase promoting complex (APC)/C Ub ligase

18
Q

What is the APC/C?

A

Anaphase promoting complex which is a mitotic E3 Ub ligase, catalysing transfer of Ub from E2 to substrate.

It contains 15 core subunits and 2 adaptors: Cdc20 or Cdh1

19
Q

What is the main function of the spindle asembly checkpoint?

A

It keeps APC/C off until all chromosomes are properly attached thus preventing anaphase entry

20
Q

What are the key proteins involved in the spindle assembly checkpoint?

A 
Mad1
Mad2
Bub1
BubR1/Mad3
Bub3
Mps1
Aurora B
21
Q

Outline the spindle assembly checkpoint pathway

A
  1. MAD1 directly recognises the unrecruited kinetochore
  2. MAD1 recruits MAD2 and activates it
  3. MAD2 forms a complex with Cdc20 preventing Cdc20 from activating APC/C

OR

  1. BubR1 acts as a substrate binding to Cdc20 and blocking substrate recruitment through competitive inhibition
22
Q

What is the function of Aurora B in the spindle assembly checkpoint?

A

Phosphorylates syntelic atttachments, causing the kinetochore to be released

23
Q

What type of incorrect chromosome attachment is poorly recognised by the spindle assembly checkpoint?

A

Merotelic attachment

24
Q

How was spindle assembly checkpoint signalling discovered?

A

Through laser ablation and micromanipulation

25
Q

What is the KMN network?

A

Complex of KNL1, Mis12 and Ndc 80 which forms around kinetochores as the cells enter mitosis

26
Q

What is the RZZ complex?

A

Zw10, Rod and Zuilch

27
Q

What causes mosaic variegated aneuploidy?

A

A germline mutation in BubR1

28
Q

How is Mad2 silenced in breast and other cancers?

A

Hypermethylated promoter

Other epigenetic mechanisms

29
Q

What does Mad2 haploinsufficiency cause?

A

CIN

30
Q

Give an example of a drug that interferes with microtubule dynamics

A

Taxanes e.g. Taxol

Vinca Alkaloids e.g. Vincristine, Vinblastine

31
Q

How do Taxanes work?

A

They stabilize microtubules and thus prevent normal mitotic spindle dynamics and activate the spindle assembly checkpoint

32
Q

How do vinca alkaloids work?

A

They depolymerise microtubules preventing spindle assembly

33
Q

What types of cancer are anti-microtubule therapeutics commonly used to target?

A

Breast, ovarian, lung and haemotological cancers

34
Q

Give an example of a side effect caused by an anti-microtubule therapeutic

A

Neurotoxicity (loss of sensation in the peripheral tissues) due to neuronal trafficking interference

35
Q

Give an example of a TF that activates the cyclin B1 promoter

A

NF-Y
Fox 1
B-Myb

36
Q

What is hysteresis?

A

the phenomenon in which the value of a physical property lags behind changes in the effect causing it, as for instance when magnetic induction lags behind the magnetizing force.

37
Q

What is hysteresis in the SAC?

A

The threshold for activation is much higher than that for inactivation of anaphase

38
Q

What possible targets have recently emerged for anti-mitotic therapy?

A

Kinesin spindle protein

Centromeric protein E

39
Q

What is KSP?

A

Kinesin spindle protein which is required to establish mitotic-spindle bipolarity

40
Q

Give an example of a KSP inhibitor?

A

Monatol

Isperinib

41
Q

What is CENPE?

A

Centromeric protein E which is required for accurate chromosome congression at metaphase

BS3003 (26 decks)

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