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Oncology > Chapter 5: The cell cycle (Book) > Flashcards

Chapter 5: The cell cycle (Book) Flashcards

1
Q

What is the average length of the cell cycle?

A

16 hours (15 h for interphase and 1 h for mitosis)

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2
Q

Are chromosomes visible in interphase?

A

No, only during mitosis.

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3
Q

What cyclin gene is a final target of the EGF signaling pathway?

A

Cyclin D gene

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4
Q

Fill in: Cyclin … (1) is the first cyclin to be synthesized and, together with CDK…(2), drives progression through … (3) phase.

A
  1. D 2. 4/6 3. G1
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5
Q

Fill in: Cyclin … (1) plays a role in the regulation of expression of the cyclin E gene, whose product is important for the … (2)-…(3) phase transition. Cyclin … (4) together with CDK2 is important for … (5) phase progression. Cyclins … (6) and … (B)-CDK1 directs … (7) phase and the … (8) to … (9) phase transition.

A
  1. D 2. G1 3. S 4. A 5. S 6. A 7. B 8. G2 9. M
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6
Q

The G1 checkpoint leads to the arrest of the cell cycle in response to…

A

DNA damage. Ensuring that DNA damage is not replicated during S phase.

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7
Q

The G2 checkpoint leads to the arrest of the cell cycle in response to…

A

damaged and/or unreplicated DNA to ensure proper completion of S phase.

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8
Q

The M checkpoint leads to the arrest of chromosomal segregation in response to…

A

misaligment of the mitotic spindle.

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9
Q

What process is an important mechanism for resetting the cell for another round of the cell cycle?

A

Dephosphorylation

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10
Q

What’s one way to identify substrates of CDKs?

A

Cross-link proteins, carry out immunopurification of protein kinases and use mass spectroscopic analysis to identifiy associated proteins. Another method for this is to screen cDNA expression libraries using a solid-phase phosphorylation assay.

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11
Q

Are CDKs tyrosine or serine/threonine kinases?

A

serine/threonine

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12
Q

What two families of inhibitors are involved in regulating cyclin-cdk activity?

A

p16 (INK) family and the p21 (Cip/Kip) family.

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13
Q

What amino acids located within ATP-binding site of the cdk can be phosphorylated? What is the result of this phosphorylation?

A

Thr14 and Tyr15. Phosphorylation of these sites psyhically interferes with ATP binding.

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14
Q

What two steps are required for CDKs to become active?

A
  1. Dephosphorylation of the inhibitory phosphate groups by cdc25 phosphatases. 2. Phosphorylation of a central threonine residue (Thr161), by cdk-activating kinase (CAK).
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15
Q

What is a key substrate of the cyclin D-cdk 4/6 complex?

A

Rb protein (important tumor suppressor protein).

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16
Q

What’s MPF?

A

Mitosis-promoting factor or so to say a cyclin-cdk complex.

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17
Q

There are four mechanisms of CDK regulation. What are these?

A
  1. Association with cyclins.
  2. Association with cdk inhibitors
  3. Addition of phosphate groups that activate CDK activity
  4. Addition of phosphate groups that inhibit CDK activity.
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18
Q

What does the binding of cyclins to their partner CDK cause?

A

A (crucial) conformational change in the CDK that allows binding of a protein substrate and correct positioning of ATP.

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19
Q

How are cyclins degraded?

A

Degradation is carried out by the proteasome through ubiquitination.

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20
Q

What is the function of the p16 (INK) and p21 (Cip/Kip)?

A

The INK inhibitors bind CDKs 4/6 and interfere with their binding to cyclin D. p21 inhibitors interact with both cyclins and their associated CDKs and block the ATP-binding site, thus disabling kinase activity.

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21
Q

What kinase (tyrosine or serine/threonine) can phosphorylate Thr15 and Tyr15?

A

The tyrosine kinase wee1.

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22
Q

Is the association of a cyclin with their CDK enough to lead to full activation?

A

No, it specifically requires phosphorylation of a central threonine residue (Thr161), by CDK-activating kinase (CAK). (Keep in mind that CAK-activity is constant throughout the cell cycle).

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23
Q

Rb, an important tumor suppressor protein, serves as a molecular link for…

A

the G1-S phase transition

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24
Q

This figure is already discussed in detail in the flashcards about the lecture and therefore will not (or briefly) be discussed. Just a reminder.

A

:)

25
Q

What is HDAC?

A

Histone deacetylase

26
Q

By what is the interaction between RB and E2F and HDACs regulated?

A

By serine/threonine phosphorylation.

27
Q

What does it mean when RB is in a hypophosphorylated state?

A

It does not have many phosphates attached and binds to both E2F and HDAC. (which prevents E2F interaction with transcription factors).

28
Q

What does activation of E2F also influence?

A

Later cell cycle events, like the production of the spindle assembly checkpoint protein MAD2.

29
Q

The G2 checkpoint blocks entry into M phase in cells that have incurred DNA damage in previous phases or have not correctly completed S phase. Specific proteins are important in the transition from G2- to M-phase. What are these?

A

cdc25 tyrosine phosphatases.

30
Q

What happens when DNA damage gets sensed during G2 checkpoint?

A

It acitvates one of two kinases, ATR or ATM. These kinases phosphorylate and activate checkpoint kinases Chk1 and Chk2. Chk1 targets Cdc25 tyrosine phosphatase. Activation of the G2 checkpoint will activate Chk1 and inhibits Cdc25. This blocks the removal of an inhibitory phosphate on CDK, therefore CDK remains inactive, preventing mitosis.

31
Q

Full activation of Chk1 requires the phosphorylation of ATR or ATM. But it also requires interaction with a mediator protein. What protein?

A

Claspin

32
Q

After succesful DNA repair, cells re-enter the cell cycle in a process called checkpoint recovery. How is checkpoint recovery (of G2 checkpoint) regulated?

A

A protein PIk1 targets claspin and wee1 for degradation and directly inhibits Chk2.

33
Q

What is another process that occurs in G2 checkpoint?

A

Decatenation -> detangling of intertwined daughter chromatids after DNA synthesis. This process enables chromatid separation during anaphase.

34
Q

What enzyme is important in decatenation G2 checkpoint?

A

Topoisomerase II, can make double-strand DNA breaks to allow unwinding.

35
Q

What is the function of the mitotic checkpoint?

A

It ensures correct chromosomal segregation during mitosis and the production of two genetically identical nuclei.

36
Q

What happens when chromatid pairs have not (yet) been attached to spindle microtubules in metaphase?

A

These unattached chromatid pairs recruit several checkpoint proteins that produce inhibitors of anaphase-promoting complex. This complex targets specific proteins for degradation in order for anaphase to begin.

37
Q

What happens when a chromatid pair is attached to the spindle?

A

The inhibition of the anaphase-promoting complex stops.

38
Q

What is a crucial target protein of the anaphase-promoting complex? Why?

A

Securin, when its degraded the protease separase is activated. Separase cleaves a protein link between sister chromatids, allowing them to separate during anaphase. (Cyclins are also targets of the anaphase-promoting complex)

39
Q

What’s the function of the aurora kinases A, B and C (also knows as STK15, STK12 and STK13)?

A

They regulate aspects of mitosis, like chromosome segregation and spindle checkpoint.

40
Q

Are Aurora kinases tyrosine or serine/threonine kinases

A

Serine/threonine

41
Q

What proteins can aurora kinases phosphorylate?

A

Histone H3

42
Q

What is the function of Aurora kinase A?

A

Aurora kinase A localizes to centrosomes during interphase (suggests a role in centrosome maturation and assembly of the mitotic spindle).

43
Q

What is the function of Aurora kinase B?

A

Aurora kinase B localizes first with centromeres, then with the middle of the spindle and later between dividing cells (in mitosis). (Suggests a role in bipolar spindle attachment to chromosomal centromers, the spindle checkpoint and monitoring of chromosomal segregation and cytokinesis).

44
Q

What is the function of Aurora kinase C?

A

Is active during late mitosis and localizes in the spindle poles.

45
Q

Alterations in cell cycle regulation in cancer include…

A

overexpression of cycins (e.g. cyclins D and E) by gene amplification.

46
Q

What method is used to detect gene amplification?

A

Fluorescence in situ hybridization (FISH)

47
Q

What does experimental evidence suggest about the fact that cyclin D mRNA and protein levels are overexpressed in 50% of breast cancers?

A

The gene for cyclin D is a proto-oncogene (both EGFR and estrogen exert their mitogenic effect by transcriptional activation of cyclin D).

48
Q

How does cyclin D enhance ER (estrogren)-mediated transcription?

A

By binding to the hormone-binding domain of ER and increasing protein interactions with ER co-activators.

49
Q

What does loss/deletion of the gene coding for the inhibitor p16 result in?

A

Increased incidence of spontaneous and carcinogen-induced cancers (like asbestos exposure).

50
Q

What does a defect in the decatenation G2 checkpoint result in?

A

It is associated with chromosome breakage and may lead to genetic instability.

51
Q

What is most common in human solid tumors?

A

Aneuploidy

52
Q

What evidence has been found (which of the two is true/false)? 1. Mutations in genes that code for components of the mitotic spindle are common in human tumor cells. 2. A decreased quantitiy of mitotic checkpoint proteins is seen in aneuploidy tumor cells with an aberrant mitotic checkpoint.

A
  1. is false (mutations in genes coding for components of the mitotic spindle are not common in tumor cells 2. is true
53
Q

What kinases are frequently overexpressed in tumors, like lymphomas?

A

The Aurora kinases

54
Q

What is the function of a semi-synthetic flavonoid called flavopiridol?

A

It’s a first-generation cdk inhibitor (non-selective). It acts as a competitive inhibitor of many cdks (1, 2, 4, 6, 7, 9) by targeting their ATP-binding site. It induces cell cycle arrest at G1/S and G2/M phases.

55
Q

Cdk inhibitors like flavopiridol don’t seem to work really well on their own. With what can they work?

A

They are synergistic with cytotoxic drugs.

56
Q

What is the function of seliciclib and dinaciclib (are/were in clinical trial)?

A

Seliciclib targets ATP-binding sites of specific cdks 2, 7 and 9. Dinaciclib targets ATP-binding sites of specific cdks 1, 2, 5 and 9.

57
Q

What, besides cdk inhibitors, are other anticancer strategies?

A

Cell cycle checkpoint kinase inhibitors against Chk1 and Chk or inhibitors of Aurora kinases.

58
Q

Fill in paclitaxel/taxol OR vinca alkaloids (vinblastine, vincristine). …. stabalize microtubules, while …. inhibit microtubule assembly.

A

Paclitaxel/taxol and vinca alkaloids (vinblastine, vincristine) respectively.

Oncology (18 decks)

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