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BIOM 4150 Cancer Biology > Unit 4- Control of Cell Cycle & Cell Death > Flashcards

Unit 4- Control of Cell Cycle & Cell Death Flashcards

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1
Q

How is the cell cycle regulated?

A
  • external signals influence the cell cycle clock
    Anti-Mitogenic signal > enter G0/ quiescent phase
    Pro-Mitogenic signal > enter active cell cycle (G1>S>G2>M)
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2
Q

What are the phases of the mammalian cell cycle?

A

G0- Non-proliferative/ Quiescent phase
G1- Proliferation decision
S- DNA replication
G2- Preparation for mitosis
M- Mitosis

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3
Q

What are the cell cycle checkpoints?

A

Start Checkpoint- is environment favourable > proceed to S phase
G2/M Checkpoint- is all DNA replicated > enter mitosis

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4
Q

What does cell cycle progression rely on?

A
  • protein presence
  • protein localization (cytoplasm vs nucleus)
  • protein activation status (phosphorylated ext)
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5
Q

What are cyclins?

A
  • cell cycle proteins that bind to CDKs to activate them/ modulate phosphorylating ability
  • undergo cyclic destruction/ synthesis
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6
Q

What are the types of cyclins?

A

G1 Cyclins- bind CDKs at G1/ promote entry into S phase
Mitotic Cyclins- bind CDKs at G2/ promote entry into M

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7
Q

What are CDKS?

A

CDK= Cyclin Dependent Kinase
- phosphorylate substrates on serine/ threonine residues

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8
Q

What are CKIs?

A

CKI = Cyclin-Dependent Kinase Inhibitor
- interfere with Cyclin/CDK complexes (binding/ phosphorylation)

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9
Q

What are the 2 families of CKIs?

A

Cip/Kip- involved in G1 and G1/S control
Ink4- involved in G1/S control

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10
Q

How do tumor suppressor/ oncogene mutations cause cancer?

A

Tumor Suppressor mutation > loss of function (brakes)
Oncogene mutation > gain of function (growth)

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11
Q

How is progression through cell cycle checkpoints regulated?

A
  • regulated by CDKs
  • depend on regulatory subunit cyclin for activity
  • different CDK/cyclin pairs throughout cell cycle > different substrates
    > cyclin levels change rapidly throughout cell cycle (1 direction cycle)
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12
Q

What ensures the cell cycle occurs in only 1 direction?

A
  • rapid changes in cyclin levels throughout the cell cycle
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13
Q

How are cyclin LEVELS regulated?

A
  • Ubiquitin ligase enzyme promotes ubiquitylation
  • adds ubiquitin to phosphorylated cyclins
    > targets cyclin protein for degradation by proteasome
  • ensures rapid/ regulated reduction in CDK activity
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14
Q

How is cyclin ACTIVITY regulated?

A
  • CDK/cyclin complexes are functionally regulated by CKIs
    INK4- regulate cyclin D complex (G1)
    Cip/Kip- regulate other cyclin complexes
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15
Q

How can CKIs regulate growth inhibition/ growth promotion?

A
  • inhibitory factors like TGFβ trigger ↑ expression of CKIs
    > growth inhibition
  • mitogens phosphorylate CKIs > phosphorylated CKIs can not translocate to nucleus/ inhibit CDK-cyclin complexes
    > growth promotion
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16
Q

What is the period where cells are responsive to mitogenic GFs/ inhibitory TGFβ?

A

G1 (up until R point)

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17
Q

What is the R-point?

A

Restriction Point- once cell passes, fully commits to cell cycle
- late in G1
- cell commits to a) advance through cell cycle/ b) remain in G1/ c) retreat from active cell cycle into G0
- deregulation of R-point in many cancers

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18
Q

What drives cells through the restriction point?

A

Pocket Proteins = RB Retinoblastoma proteins
- tumor suppressors (lack of functional gene > eye tumors)
- phosphorylation state of pRb influences activity
- hyperphosphorylation of pRB required for transition through R point
- pRb binds to E2F family transcription factors/ inhibit activity

19
Q

How does the phosphorylation status of pRb (pocket protein) influence the cell cycle?

A

Hyperphosphorylated pRb = inactive/ can not bind and inhibit E2F transcription factors
- cyclin activity leads to ↑ pRB phosphorylation > bypass G1 R-point
- pRb becomes more phosphorylated as cell cycle progresses

Early-mid G1- unphosphorylated > hypophosphorylated
Late GI- hypophosphorylated > hyperphosphorylated

20
Q

How is the R point perturbated in cancer?

A
  • oncogenes promote advancement through restriction point ex) Myc
  • tumor suppressors block advancement through restriction point
21
Q

What are the steps in DNA damage repair?

A
  1. DNA lesion detection
  2. Recruitment of DNA-repair factors
  3. Activation of DNA-repair enzymes
  4. Repair
  5. Degradation/ inactivation of DNA repair factors
22
Q

What are the potential consequences of DNA damage in cell cycle?

A

Repair/ Apoptosis/ Senescence/ Mutation

23
Q

What is a drug developed to target the cell cycle?

A

Palbociclib = selective CD4/6 small molecule inhibitor
- initial attempts to target CDKs failed due to broad actions against all CDKS (poor specificity > high toxicity)
- RB deficient tumors do not respond/ tumors can become resistant

24
Q

What is the difference between Necrosis/ Apoptosis?

A

Necrosis- pathological/ uncontrolled/ induced by ROS, trauma/ tissue damage/ neighbouring cells affected/ membrane disruption/ cell swells

Apoptosis- controlled cell death/ no inflammation/ no tissue damage/ surrounding cells normal/ induced by specific signaling or cell stress

25
Q

What are 3 apoptosis assays?

  • caspases are key molecules in apoptosis
A

Phosphatidylserine/ Annexin V staining
- recognition signal for macrophage engulfment

TUNEL Assay
- addition of labeled nucleotides > nicked DNA
- not specific to apoptosis (labels any fragmented DNA)

Immunostaining for activated Caspase 3
- requires antibodies that only recognize caspase 3

26
Q

What are the 2 major apoptosis pathways?

A

Intrinsic (mitochondrial) / Extrinsic (death receptor)
- converge at execution phase of apoptosis

27
Q

What are the 2 types of caspases?

A

Initiator- detect/ transduce signals/ activate effector caspases/ protein-protein interactions
Effector = Executioners- cleave downstream targets > cell death

28
Q

What is the caspase paradox?

A
  • caspases cleave substrates at Asp-X-X-Asp
  • caspase activation requires cleavage at Asp-X-X-Asp
29
Q

What is APAF-1?

A
  • assembles into apoptosome (wheel of death) to activate caspases
  • several domains including CARD for protein interactions
30
Q

How are apoptosomes formed?

A
  • Cytochrome C interacts with bound ATP, inducing hydrolysis to ADP
  • results in conformational change in APAF-1
    > exposure of CARD domain > interact with each other > complex forms
    (many APAF-1s come together to form an apoptosome)
  • ADP/ATP swap allows APAF-1 molecules to assemble > apoptosome by binding ar CARD domains
31
Q

How does caspase activation work?

A
  • procaspase 9 binds via CARD to apoptosome
  • more CARD bound procaspase 9’s recruited > antiparallel orientation
  • leads to autoactivation of apoptosome-bound caspase 9
    > caspase cascade leading to apoptosis
32
Q

How does Cytochrome C induce apoptosis?

A
  • cytochrome c sequestered in intermembrane space of mitochondria
  • release triggered by pro-apoptotic events > leads to activation of procaspase 9 ext
  • cytochrome c release also occurs with mitochondrial damage
33
Q

What is the Fas/FasL pathway?

A
  • Fas ligand binds to receptor > assembly of DISC
    > activation/cleavage of procaspase 8/10 > activation of executioners
34
Q

How is procaspase 8 activated?

A
  • initial ligand-receptor interactions > clustering
  • recruitment of FADD proteins > large clusters of FAS/FASL
    > DISC assembly (DISC is like apoptosome) > activate procaspases
35
Q

How is the mitochondrial pathway activated?

A
  • active caspase 8 > cleavage of Bid
  • truncated Bid > induces cytochrome c release from mitochondria
  • cytochrome c enhances activation of effector caspases
36
Q

What are the 2 main protein groups of Bcl-2 family?

A

Pro-Survival > Bcl-2/ Bcl-x
- maintain integrity of mitochondrial membrane/ prevent cytochrome c release (protect cells from apoptosis)

Pro-Apoptotic> Bax/ Bak/ Bad/ Bim/ Noxa/ Puma
- promote cytochrome c release from mitochondria (tumor suppressors)

37
Q

What is the only cytotoxic/pore-forming Bcl-2 protein?

A

Bax members (Bax/Bak)

38
Q

How do Bcl-2 proteins work/ how do they promote apoptosis?

A

Bax/Bak = pore-forming (pro-apoptotic)
- actively inhibited by Bcl-2/Bcl-x (pro-survival)

BH3 Only family (pro-apoptotic Bcl-2’s not including Bax/Bak inhibit prosurvival members (Bcl-2/Bcl-x)

  • inhibition of inhibitors > pro-apoptotic events
39
Q

How are BH3 only proteins regulated?

A

Bim/ Bid/ Bad > Post-translational mechanisms
Puma/ Noxa > De novo expression
- gene expression controlled by p53

40
Q

How does p53 contribute to cancer?

A
  • master transcription factor, gene promoters contain p53 binding sites
  • loss of function of p53 rather than loss of protein (mutations)
  • pro-apoptotic protein prone to inactivation
41
Q

How does p53 induce apoptosis?

A
  • Fas production > activation of procaspase 8
  • Bax production > ↑ release of cytochrome c from mitochondria
42
Q

What is a question about p53?

A
  • is main oncogenic action via interference with p63/p73?
    (mutant p53 interferes with p63/p73 binding to gene promoters)
43
Q

What is anoikis?

A
  • loss of ECM (cell: matrix) / cell: cell adhesion > metastasis
  • PKB-AKT signaling has key role in cell death
44
Q

What is the UPR?

A
  • unfolded protein response > to reduce ER stress
  • if persists can trigger apoptosis/ mutation

BIOM 4150 Cancer Biology (6 decks)

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