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PATH3309 > 8 - Control of Cell Proliferation > Flashcards

8 - Control of Cell Proliferation Flashcards

1
Q

Cell Proliferation

A
  • Cell division
  • Regulated / controlled by signals outside (e.g growth factors, nutrient availability) and inside (e.g. signalling pathway activity) the cell
  • Loss or abnormalities of control of cell proliferation
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2
Q

Phases of cell cycle

A

-G1
- S
- G2
- M
- G0

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3
Q

G0

A

Non-proliferating state of cells. (resting cells, cells that have withdrawn from the cell cycle)

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4
Q

Cell cycle checkpoints

A

Places where the cell cycle can be arrested to ensure faithful cell replication

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5
Q

Restriction point

A
  • Part of (late) G1 where cells commit to cell division
  • During G1, cells are responsive to external factors (eg. growth factors) which can either
    promote progression through G1 or promote cell cycle exit (G0)
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6
Q

Regulation of cell cycle progression

A

Regulated by cyclin dependent kinases (CDKs)

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7
Q

CDKs

A

Serine/threonine kinases (phosphorylate other proteins on serines/threonines)
- Function (and appropriate target recognition) is dependent on cyclins
- Cell cycle progression occurs via sequential activation / inactivation of CDK/cyclin complexes

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8
Q

CDK / cyclin complexes in G1 phase

A

CDK4/6 : Cyclin D1, D2 or D3

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9
Q

CDK / cyclin complexes in late G1 phase (after R point)

A

CDK2 : Cyclin E1 or E2

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10
Q

CDK / cyclin complexes in S phase entry

A

CDK2 : Cyclin A1 or A2

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11
Q

CDK / cyclin complexes in late S phase

A

CDK1 : Cyclin A1 or A2

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12
Q

CDK / cyclin complexes in G2 / onset of mitosis

A

CDK1 : Cyclin B1 or B2

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13
Q

Regulation of activity of cyclin - CDK complexes

A
  • Regulated by CDK inhibitors (CDKIs)
  • Two classes are INK4 and Cip/Kip inhibitors
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14
Q

Ink4 Inhibitors

A

Inhibitors of CDK4 and CDK6 by:
- Distorting the cyclin D
binding site, reducing
affinity for cyclin D binding.
- Distort ATP binding site, reducing enzymatic activity

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15
Q

Examples of Ink4 inhibitors

A
  • p15
  • p16
  • p18
  • p19
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16
Q

Cip/Kip

A
  • Bind all cyclin-CDK complexes
  • Promote the formation of CDK4/6-cyclin D complexes
  • Function by blocking the ATP binding site in the catalytic cleft of the CDK
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17
Q

Examples of Cip/Kip inhibitors

A
  • p21
  • p27
  • p57
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18
Q

Early G1

A
  • Low levels of cyclins
  • High levels of p21/p27
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19
Q

Early/mid G1

A
  • Cyclin D levels increase (due to mitogenic stimuli)
  • p21/p27 bind and promote formation of Cyclin D/CDK4/6 complexes (enhances G1 progression)
  • Cyclin E/CDK2 start to increase but p21/p27 bind and inhibit CDK2 complex activity
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20
Q

Mid late G1

A
  • Cyclin E/CDK2 start to increase but p21/p27 bind and inhibit CDK2 complex activity
  • Prevents premature S phase entry
21
Q

Late G1

A
  • Cyclin E/CDK2 levels continue to increase and there isn’t enough p21/p27 to inhibit activity
  • CDK2 becomes activated & phosphorylates p27,
    targeting it for ubiquitin-mediated degradation
  • Lack of CDK inhibitors promotes S phase entry
22
Q

Retinoblastoma protein (RB)

A
  • Negative regulator of G1-S transition
  • RB, p107, p130
  • Hypophosphorylated in
    early/middle G1
  • Becomes progressively
    phosphorylated by activated CDKs during G1 and throughout the remainder of the cell cycle
  • Hyperphosphorylation of RB inactivates it allowing cell cycle progression
23
Q

Hypophosphorylated RB

A
  • Binds E2F complexes which are bound to the promotors of target genes
  • Recruits histone deacetylases (HDACs)
  • HDACs remove acetyl groups from histones
  • Deacetylated histones are associated with
    closed chromatin = repressed transcription
24
Q

Hyperphosphorylated RB

A
  • Does NOT bind E2F complexes
  • Lack of RB enables histone acetylases
    (HATs) to bind E2F complexes
  • Histones become acetylated, chromatin
    opens = activation of target gene transcription
25
Q

RB in late G1

A
  • In late G1, Cyclin E/CDK2 activity increases and phosphorylates RB
  • RB becomes hyperphosphorylated
    (inactive)
  • RB releases E2F’s
  • E2F transcriptionally activate genes required for G1/S phase progression (eg. cyclin E)
26
Q

Regulation of cell cycle regulators

A
  • MYC regulation of cell cycle regulators
  • Regulation of cyclin D1 levels by signalling pathways
  • Regulation of p21 by p53
27
Q

Regulation of G1-S transition pathways

A
  1. MYC regulation of cell cycle regulators
  2. Regulation of cyclin D1 levels
  3. Regulation of p21 expression by p53
28
Q

MYC/MIZ1

A

Represses expression of p15, p21 and p27

28
Q

MYC/MAX

A
  • Increases expression of cyclin D2
  • Increases expression of CDK4
  • Increases expression of CUL1 (which degrades p27)
  • Increases expression of E2F1, E2F2, E2F3
29
Q

MYC transcription factor

A
  • Family of bHLH TFs
  • Activates transcription in partnership with MAX
  • MAD/MAX complexes
    repress MYC target genes
30
Q

Effect of too much MYC (MYC gene amplication)

A

Promotes uncontrolled cell cycle progression

31
Q

Three examples of signalling pathways that drive cell proliferation

A
  • MAPK
  • PI3K
  • JAK/STAT
31
Q

Regulation of cyclin D1 levels

A
  • Many cell signalling pathways activate expression of cyclin D1
  • Some cancers have abnormally increased activity in signalling pathways which drives cancer proliferation (e.g. HER2 gene amplification in breast cancer)
32
Q

p53

A
  • Transcription factor
  • Functions as a homotetramer
  • Is activated following DNA damage
  • Upregulates p21 expression to arrest cell proliferation until
    DNA damage is repaired, or to induce cell death
33
Q

Loss of p53

A
  • Most common events in human cancer
  • CAn occur via gene deletion, or by acquisition of inactivating mutations
34
Q

Control of proliferation in cancer cells

A
  • Cancer cells proliferate more rapidly than non malignant cells due to defects in cell cycle control
  • Less responsive to the external environment (growth factors, other cells)
35
Q

Oncogenes

A

Genes/proteins that activate normal cell proliferation, but are mutated/activated in cancer resulting in uncontrolled proliferation

36
Q

Tumour suppressor genes

A

Genes/proteins that normally prevent cell proliferation, but are mutated/inactivated in cancer resulting in uncontrolled proliferation

37
Q

Examples of oncogenes

A
  • MYC
  • RAS
  • EGFR
  • HER2
38
Q

Examples of tumour suppressor genes

A
  • TP53 (encodes p53)
  • RB
  • CDKN2A
39
Q

D type cyclin mutations

A
  • Overexpression &/or gene amplification
  • Hyperactivity of signaling pathways
  • Reduced degradation
40
Q

D type cyclins consequence

A

Increased G1-S phase progression in the absence of real mitogenic stimuli

41
Q

E type cyclin mutations

A
  • Gene amplification &/or overexpression
  • Reduced degradation
42
Q

E type cyclin consequence

A

Increased G1-S phase progression

43
Q

Targeting cell cycle for cancer therapy

A
  • Some cancer treatments target rapidly proliferating cells BUT these treatments also affect non malignant cells (e.g. cells lining gut, hair follicle cells)
44
Q

Drugs that target G1 - S phase transition

A
  • Antimetabolites
  • Topoisomerase II inhibitors
45
Q

Drug names ending in ‘ciclib’

A

Indicate they are cyclin dependent kinase inhibtors

46
Q

Abnormal cell proliferation

A
  • Hallmark of cancer
  • May be due to mutations in cell cycle regulatory proteins or abnormal regulation of cell cycle regulators (e.g. cell death regulation, signalling pathway activity, DNA repair mechanisms)
47
Q

What is cell cycle progression / inhibitions regulated by

A
  • Control of cell death
  • DNA repair
  • Activation / inhibition of signalling pathways
  • Telomerase activity
    -Function of tumour suppressor genes / oncogenes

PATH3309 (12 decks)

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