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

Chapter 5: The cell cycle (Lecture) Flashcards

1
Q

What is the cell cycle?

A

The process that cells progress through in order to proliferate. It is key to development and homeostasis.

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2
Q

What can dysfunction in cell cycle control lead to?

A

Uncontrolled cell proliferation or errors during the cell cycle (–> mutations).

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3
Q

What is meant by “omnis cellula e cellula”?

A

All cells arise only from pre-existing cells (there’s also a spontaneous generation theory)

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4
Q

What is the main goal of the cell cycle?

A

To generate two identical daughter cells out of a single progenitor cell.

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5
Q

How is this main goal of generating identical daughter cells out of a single progenitor achieved?

A

Through DNA replication (step 1) and partitioning of the duplicated genome into two new cells (step 2).

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6
Q

Describe the cell cycle in short.

A
  • Most cells are in the G0-phase (quiescent state). From here cells can enter the cell cycle at G1.
  • In G1-phase (gap phase) there’s preparation and control (whether there’s the right metabolic conditions).
  • In S-phase there’s DNA replication (1 sister chromatide -> pair of sister chromatides)
  • In G2-phase there’s preparation and control that prior processes have went well.
  • In M-phase there’s mitosis -> cell and chromatide partitioning.
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7
Q

What happens in the S-phase?

A

Duplication of each chromosome by DNA replication. Machinery ensure error free replication, at the right time.

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8
Q

What is normally a signal for cells in the G0-phase to re-enter the cell cycle?

A

The presence of mitogens

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9
Q

What is meant by the interphase?

A

All the phases except mitoses. So if a cell is in interphase, it just means it’s not in the M-phase.

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10
Q

How are sister chromatides held together after the S-phase?

A

Bij ring-like structures called cohesins

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11
Q

How is chromosome partioning achieved in mitosis?

A

Chromosomes are physically moved and segregated by a large, dynamic machine made up of microtubule polymers, the mitotic spindle.

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12
Q

Name the phases in mitosis.

A

Prophase - Prometaphase - Metaphase - Anaphase - Telophase/Cytokinesis

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13
Q

What happens in the prophase?

A

Individual chromosomes slowly become visible and the mitotic spindle is starting to form.

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14
Q

What happens in the prometaphase?

A

The mitotic spindle is visibly forming and the chromosomes are still scattered around.

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15
Q

What happens in the metaphase?

A

The chromosomes are lined in the middle of the cell.

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16
Q

What happens in the anaphase?

A

The chromosomes are separated by the mitotic spindle.

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17
Q

What happens in the telophase/cytokinesis?

A

Two cells are starting to form which will seperate.

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18
Q

What is the first and second grow/gap phase (Grow Phase 1 and 2)?

A
  • Grow phase 1 happens in the G1-phase, here mitogenic signals are being sensed and nucleotides being made.
  • Grow phase 2 happens in the G2-phase.
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19
Q

How is order established (i.e. what are the engines that drive the cycle?

A

Key to cell cycle control are CDKs (Cyclin-dependent Kinases).

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20
Q

What is the function/influence of CDKs?

A

CDKs phosphorylate substrates, these define where the cell cycle cells are. Fluctuating activities of these kinases thus drive cell cycle transitions and processes.

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21
Q

CDKs need another protein to fulfill their kinase function. What protein?

A

Cyclins, different CDKs associate with defined Cyclins and are needed for specific cell cycle phases.

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22
Q

What CDKs are needed for the G1-phase? Also name CDKs needed for S-phase and G2/M-phase.

A
  • G1-phase -> CDK4/6
  • S-phase -> CDK2
  • G2/M-phase -> CDK1
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23
Q

Cyclin levels fluctuate during the cell cycle. What determines these levels?

A

Transcriptional activity (cyclin availability) as well as proteolytic degradation (ubiquitin-mediated proteolysis).

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24
Q

During the cell cycle different cyclins are present. Name these.

A

Cyclin E, A, D and B.

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25
Q

During the cell cycle different cyclins are present at different levels. Describe the levels of these different cyclins as the cell cycle phases progress.

A
  • Cyclin D is present during all the phases (highest in S-phase)
  • Cyclin E is present during the transition from G1- to S-phase.
  • Cyclin A is present from G1 to beginning of mitosis (highest during G2-phase)
  • Cyclin B is present from S-phase to in the middle of mitosis.
26
Q

What are two ways to make Cyclin-CDK complexes inactive?

A

Association with CDK-inhibitors (CDKi’s) (like p16 and p21) or through phosphoregulation.

27
Q

What is phosphoregulation?

A

Regulation of the phosphorylation levels on Cyclin-CDK complexes. There are certain kinases (Wee1/Myt1 or CAK) and phosphatases (Cdc25) that can phosphorylate these complexes.

28
Q

What “p-proteins” can interfere with Cyclin binding?

A

(members of the family of) p16, 15, 18 and 19.

29
Q

What “p-proteins” can interfere with ATP binding and kinase function?

A

(members of the family of) p57, 27 and 21.

30
Q

The “p-proteins” that interfere with cyclin binding, can only inhibit certain CDKs. Which?

A

CDK4/6

31
Q

The “p-proteins” that interfere with ATP-binding and kinase function, can only inhibit certain CDKs. Which?

A

two complexes of CDK2 (A-CDK2 and E-CDK2) and two complexes of CDK1 (A-CDK1 and B-CDK1)

32
Q

There are certain checkpoints for control of transitions. When are these checkpoints?

A

During mitosis, G1-restriction point and inbetween G1-S phase and G2-M phase.

33
Q

What is controlled during these checkpoints?

A
  • During mitosis -> correct chromosome segregation? - G1-restriction point –> favorable conditions for S-phase? - Inbetween G1-S phase –> DNA integrity? - Inbetween G2-M phase –> DNA integrity?
34
Q

What transcription factor drives certain programs required for S-phase?

A

E2F

35
Q

What is the target of E2F?

A

Cyclin E and A and S-phase genes (thymidylate synthase, and dihydrofolate reductase)

36
Q

How is E2F inhibited?

A

Retinoblastoma (Rb) protein is an inhibitor of E2F and binds with it. It also recruits HDAC (which prevents release of E2F).

37
Q

What can phosphorylate Rb? And what happens after phosphorylation of Rb?

A

Rb is phosphorylated by Cyclin D/CDK4 complex, which leads to the release of HDAC and subsequent transcription of cyclin E.

38
Q

How are S-phase genes stimulated to be transcribed?

A

When cyclin E is transcribed and froms a complex with CDK2, it can again phosphorylate Rb. This promotes full activation of E2F, where E2F can than stimulate transcription of S-phase genes.

39
Q

How is S-phase activation prevented when cells experience genotoxic stress?

A

Through a p53-p21-dependent pathway, which prevents Cyclin E/CDK2 activation.

40
Q

What are key components of G2-M checkpoint?

A

ATM and ATR kinases

41
Q

What is the eventual downstream effect of these kinases (ATM and ATR)?

A

Inhibition of CDK activitiy (Cyclin B/CDK1), via phosphorylation.

42
Q

What is the mitotic checkpoint?

A

Checkpoint if all chromosomes are properly attached to the mitotic spindle.

43
Q

What happens if not all chromosomes are properly attached to the mitotic spindle during the mitotic checkpoint?

A

Aurora kinase ubiquitinates and tags Cyclin B for degradation.

44
Q

In what phase will cells arrest if not all chromosomes are properly attached during the mitotic checkpoint?

A

Metaphase

45
Q

Many cancer exhibit defect in checkpoint function. In what checkpoint can the most defects be found?

A

In G1-S checkpoint

46
Q

In what cancers is cyclin D upregulated?

A

Breast, head & neck, oesophagus

47
Q

In what cancers is there loss of p16?

A

Melanomas, bladder, head & neck, lung

48
Q

In what cancer is there loss of Rb?

A

Retinoblastoma osteosarcoma, prostate, breast, bladder, lung

49
Q

In what cancer is there loss of p53?

A

In most tumours.

50
Q

ATM kinase can mutate which can result in ataxia-telangiectasia. What is this?

A

A neurodegenerative disease that increases the risk of cancer (lymphoma, leukemia)

51
Q

p53 can mutate which can result in Li-Fraumeni syndrome. What is this?

A

A syndrome that increases cancer risk of carcoma, breast cancer and leukemia.

52
Q

Aurora kinase can mutate or amplificate. What does this result in?

A

Mitotic defects and aneuploidy. Increases the risk for breast, colon and pancreatic cancer.

53
Q

What is aneuploidy?

A

The incomplete segregation of chromosomes, caused by errors in chromosome segregation in mitosis.

54
Q

Are there often defects/mutations in the mitotic checkpoint?

A

No, they are rarely seen.

55
Q

Pfizer’s CDK4/6 inhibitor is approved for what kind of cancer?

A

Advanced breast cancer

56
Q

How do many classical chemotherapeutic approaches work?

A

By activating cell cycle checkpoints, as such inhibiting cellullar proliferation.

57
Q

What is a microtubule drug that can activate mitotic checkpoint?

A

Taxol, it induces mitotic arrest.

58
Q

What is the function of doxorubucin or PARP-inhibitors?

A

They trigger DNA damage which activates DNA integrity checkpoints.

59
Q

What is a more recent approach of targeting the cell cycle?

A

To target specific mutations and characteristics that define cell cyle progression (like vulnerabilities that are present in mutated situations or exposed by aneuploidy).

60
Q

In breast carcinoma there’s Cyclin E overexpression. How can this overexpression be regulated?

A

By inhibiting PKMyt1 (kinase for phosphoregulation).

61
Q
  • What are the basic machinery that drive the cell cycle?
  • What are agents that stop the cell cycle in case of defects?
  • What are specific vulnerabilities created by the inherent mutational landscape seen in cancer cells?
A
  • CDKs
  • Taxol, DNA damaging agents
  • Gene amplification, aneuploidie
62
Q

Cyclin-CDK complexes are key drivers of the cell cycle. Consider the following statements: Cyclin-CDK complex activities are controlled by:

  1. Cell cycle-regulated transcription of CDK genes
  2. Ubiquitin-mediated proteolysis of Cyclin proteins
  3. Phosphorylation/dephosphorylation of Cyclin-CDK complexes

What is correct?

A. 1., 2., and 3. are correct

B. Only 2. is correct

C. 1. and 3. are correct

D. 2. and 3. are correct

A

D. 2. and 3. are correct

Oncology (18 decks)

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