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Radiation Biology > Hall 22 - Cell, Tissue, Tumor Kinetics > Flashcards

Hall 22 - Cell, Tissue, Tumor Kinetics Flashcards

1
Q

Are Cdk levels constant throughout the cell cycle? What regulates their activity?

A

Yes
Cyclins
Cdc25 phosphatases
Cdk inhibitors

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2
Q

What cyclins are synthesized during G1>S?

A

Cyclin D + Cdk4/6
Cyclin E + Cdk2

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3
Q

What cyclins are synthesized during S>G2?

A

Cyclin A + Cdk2

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4
Q

What cyclins are synthesized during G2>M?

A

Cyclins B/A + Cdk1

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5
Q

What does Cdc25A do?

A

Removes inhibitory phosphate groups from Cdk4/6 and Cdk2 (G1/S)

Positively regulates Cdk activity (increases)

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6
Q

What does Cdc25C do?

A

Removes inhibitory phosphate groups from Cdk1 (G2)

Positively regulates Cdk activity (increases)

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7
Q

What inhibits Cdc25?

A

ATM/ATR

Phosphorylates and activates checkpoint kinases Chk1/2, which phosphorylate Cdc25 and target them for degradation

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8
Q

What two families inhibit Cdk?

A

INK4 (p16-INK4A)
Cip/Kip (p21)

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9
Q

How do INK4 family proteins inhibit Cdk?

A

p16-INK4A boosts Rb
p14-ARF inactivates MDM2 (boosts p53)

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10
Q

How do Cip/Kip family proteins inhibit Cdk?

A

p21 (Cip1) is a key p53 target gene

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11
Q

What is BMI1?

A

An oncogenic polycomb protein that is a negative regulator of INK4A/B

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12
Q

How does TGF-beta inhibit Cdks?

A

Inhibits Cdc25A activity (via Smad3/4) and increases INKs and p21

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13
Q

How does growth factor withdrawal inhibit Cdks?

A

Activates GSK-3beta > phosphorylates cyclin D and targets for degradation

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14
Q

What checkpoint is lost in cancer cells?

A

G1>S checkpoint (loss of p53 function)

Retain the intra-S and G2 to M checkpoints

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15
Q

What does Rb do at rest?

A

Inhibits E2F/DP-1 transcription factors

When Rb is phosphorylated by Cyclin D-Cdk4/6 and Cyclin E-Cdk2, the phospho-Rb and HDAC repressor complex dissociate from DNA > increase E2F/DP-1

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16
Q

What happens when Rb is phosphorylated?

A

When Rb is phosphorylated by Cyclin D-Cdk4/6 and Cyclin E-Cdk2, the phospho-Rb and HDAC repressor complex dissociate from DNA > increase E2F/DP-1

E2F drives transcription of key genes for cell cycle progression and DNA replication (including more Cyclin E = positive feedback loop)

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17
Q

How is the G1 to S checkpoint regulated?

A

DNA damage > ATM auto-phosphorylates (inactive dimer > active monomer)

> phosphorylates p53 and MDM2 to release p53 inhibition > p53 drives transcription of p21 > inhibits Cdk4/6 and Cdk2

ATM phosphorylates Chk1/2 > inhibits Cdc25A > decreased Cdk4/6 and Ckd2

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18
Q

What does p53 do?

A

Regulates G1 to S checkpoint

ATM monomer > phosphorylates p53 and MDM2 to release p53 inhibition > p53 drives transcription of p21 > inhibits Cdk4/6 and Cdk2

ATM phosphorylates Chk1/2 > inhibits Cdc25A > decreased Cdk4/6 and Ckd2

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19
Q

How does HPV abrogate the G1 to S checkpoint?

A

Inhibits both p53 and Rb with E6 and E7 viral proteins (respectively)

20
Q

What is the most variable length phase in the cell cycle?

A

G1

21
Q

What are four ways that tumors inactivate p53?

A
  1. Viral proteins: E6 (HPV), adenovirus E1B, SV40 T antigen
  2. Point mutations in p53
  3. MDM2 amplification (destabilizes p53 for ubiquitination)
  4. Loss of INK4A-ARF locus (less p14-ARF = increased MDM2 activity)
22
Q

When is Cyclin A maximally expressed?

A

S phase
Forms Cyclin A-Cdk2 complex

23
Q

What is Cdc45?

A

Crucial to loading DNA polymerase alpha onto chromatin and for replicon initiation (S phase)

24
Q

How does ATM act in intra-S phase checkpoint?

A

Phosphorylates Chk1/2 > inhibits Cdc25A > decreased Cdk2 activity

Phosphorylates NBS (in MRN) > activates SMC proteins > intra-S arrest

*If ATM or NBS is deficient, then cells have radioresistant DNA synthesis

25
Q

What drives the G2 to M transition?

A

Cyclin B-Cdk1

26
Q

What inhibits Cdk1?

A

Wee1 and Myt1

27
Q

What activates Cdk1?

A

Aurora A kinase (AurA)/Bora activates PLK1 > activates Cdc25C > activates Cdk1

28
Q

How does ATM act in G2 to M checkpoint?

A

Phosphorylates p53 (relieves MDM2 inhibition) > key target genes transcribed:

  • 14-3-3 sigma
  • GADD45
  • p21 (inhibits Cdk1)
  • Pro-apoptotic genes (Bax, Noxa, Puma)
  • PCNA
  • MDM2 (negative feedback loop)
29
Q

What co-activator complex acetylates and increases p53 in G2 to M?

A

p300/PCAF

30
Q

What does ATM phosphorylation of Chk1/2 in G2 to M do?

A

Inhibits Cdc25C > decreased Cdk1

Chk1/2 also phosphorylates p53, increasing activity, and Wee1

31
Q

How does ATR sense DNA damage?

A

Senses persistent single-stranded DNA (stalled replication forks, DSB breaks after resection of one DNA strand)

Recruited by ATRIP

Targets Wee1, Chk1 > cell cycle arrest

32
Q

What is the major protein involved in late G2?

A

ATR

*Not ATM (which is the major protein involved in response to DNA damage overall)

Regulates firing of replication origins, repair of damaged replication forks, and preventing premature mitosis

33
Q

What cell cycle checkpoint does caffeine inhibit?

A

G2 to M
(more likely to proceed to mitosis)

34
Q

What is the most important cell cycle checkpoint after radiation damage?

A

G2 to M

1 Gy in G2 = 1 hour delay in cell cycle progression

Deficient G2 checkpoint arrest = radiosensitivity (unrepaired DNA damage going into mitosis)

35
Q

What is the mitotic index?

A

Proportion of cells in mitosis at any given time

MI = λ x TM / TC

λ = 0.693, correction factor for cells doubling during mitosis
TM = length of mitosis
TC = total length of cell cycle

(provides ratio of M relative to total cell cycle length, but not absolute duration)

36
Q

What is the labeling index?

A

Proportion of cells in S phase at any given time

LI = λ x TS / TC

λ = 0.693
TS = length of S phase
TC = total length of cell cycle

(provides ratio of S relative to total cell cycle length, but not absolute duration)

37
Q

What technique can give the absolute duration of all cell cycle phases?

A

Percent labeled mitoses technique

Flash label cells and harvest/stain at periodic intervals, plot M percentage vs time

38
Q

What is the average cell cycle time TC?

A

48 hours
TS = 16 hours

~TC = 3 x TS

39
Q

What is the growth fraction?

A

Fraction of cells proliferating at any given moment

GF = P / (P+Q)

P = proliferating cells
Q = quiescent cells

GF = 30-50% in most solid tumors

40
Q

What is the potential doubling time?

A

Tpot = cell doubling time of a tumor assuming no cell loss

Tpot = TC / GF = λ x TS / LI

41
Q

What accounts for the difference between Tpot and actual tumor doubling time (Td)?

A

Cell loss

Cell loss factor φ = 1 - Tpot/Td

φ = ratio of rate of cell loss vs rate of new cell production; ~77%

42
Q

How are Tpot and Td related for smaller tumors?

A

Closer together
Td>Tpot for large tumors

43
Q

What is the most important factor determining tumor growth?

A

Cell loss

Explains why cell cycle time is short (TC ~1-5 days) but tumor doubling time is 2-3 months

44
Q

How does the cell loss factor φ change with radiation?

A

Decreases several weeks into radiation (rate of tumor regression slows)

45
Q

Summarize tumor growth in terms of GF and cell loss.

A

A minority of cells (GF) are proliferating (most are quiescent)

Most new cells produced by mitosis are lost from the tumor (inadequate O2, apoptosis, immune attack, metastasis)

Radiation Biology (29 decks)

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