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MCC > Wk 3 Cell cycle > Flashcards

Wk 3 Cell cycle Flashcards

1
Q

Interphase

A

G0, G1, S, G2

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2
Q

After mitosis

A

Did all chromosomes separate?
G0 - most cells in this state

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3
Q

How do cells know if they should divide?

A

External signals
-is DNA replication a good idea or will it cause a problem?

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4
Q

In what phase are most mistakes made?

A

S phase

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5
Q

What questions are addressed in G2?

A

Has my genome been copied exactly once?
-cancer cells copy many more times
Are my chromosomes condensed?
-cannot go back to S phase
Did DNA replication happen normally?

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6
Q

Questions during S phase

A

Is DNA replication going well? Is the new DNA intact?
-cannot go back and start over

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7
Q

When is the decision to enter the cell cycle made?

A

G0-G1 transition
-also as cell exits M and decides whether or not to go through another cycle

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8
Q

What are CDKs?

A

Cyclin-dependent kinases - drive the cell cycle forward, making events happen by phosphorylating factors
-no activity unless bound to cofactors (cyclins), which regulate based on presence and []
-always around, waiting for activation by cyclins

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9
Q

What are cyclins?

A

Cofactors for CDKs that are made periodically through the cell cycle
-they also influence the substrates of CDKs, so they are CDK activators and guidance counselors
-overexpression of an S phase cyclin will drive S phase to happen whether or not it’s appropriate

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10
Q

What happens if there’s an E3 ubiquitin ligase?

A

Something is going to die

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11
Q

What catalyzes ubiquitylation?

A

E1 (enzyme that activates Ub)
E2 (Ub conjugating)
E3 ligases (provide target recognition)
-these are part of a cascade of factors that catalyze ubiquitylation of target proteins

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12
Q

What are daisy chains?

A

Multiple ubiquitins added to target protein - typically leads to degradation
-only one Ub marks protein for activity change

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13
Q

What is DDR

A

DNA damage response
-pathway w/ tumor suppressors and proto-oncogenes
-w/ cancer, this can be ignored to continue replicating a mutation

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14
Q

What is p53?

A

Monitors DNA damage
-a transcription factor that can stop cell cycle if finds damage for repair OR it can cause apoptosis if the cell is too damaged
-can stop cyclins from turning on

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15
Q

What is MDM2?

A

a gene coded for by p53, so needs p53 to be made
-E3 ubiquitin ligase
-responsible for keeping p53 levels low
-partners w/ an E2 that’s carrying ubiquitin and goes around looking for p53 and targets it for degradation (thereby inhibiting it)

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16
Q

1 weird thing about p53 mutations

A

-most cancerous growths start out w/ a dominant negative (one mutation, bad copy, messes up the other copy…one stupid person in group -> others doubt themselves, become stupid) point mutation in TP53, but most tumors have 2 null mutations in the gene that encodes it
-> no p53 activity eventually after multiple steps (point mutations in one allele -> missense -> null (deletion) in both alleles) - occurs over time

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17
Q

Loss of heterozygosity

A

LOH means I was heterozygous, now I’m homozygous

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18
Q

What is a checkpoint?

A

Like the sign by the cliff - warnings, but could ignore it
-sign doesn’t stop the cell, just warnings and monitors to warn about dangers

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19
Q

What is the mitotic index?

A

Reflects the proliferation rate of the cells
-fraction of visible cells undergoing mitosis
-mitosis is a small part of the cycle, so the more you see in mitosis, the faster the population of cells is proliferating

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20
Q

How can we disrupt mitosis?

A

By destabilizing OR by stabilizing microtubules

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21
Q

What happens at a checkpoint?

A

Machinery that asks if everything is ok with the DNA to slow down or stop replication

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22
Q

What is the main checkpoint inhibitor?

A

p53

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23
Q

What is p21?

A

CDK- inhibitor produced by p53 that can slow down the cell cycle

24
Q

What are tumor suppressors and proto-oncogenes?

A

normal cell cycle machinery - proteins that act as cycle progression monitors
-proto-oncogenes often cyclins that become mutated to oncogenes and drive the cell cycle forward
-tumor suppressors are often cylcin-dependent kinase inhibitors that put brakes on cell cycle

25
Q

What type of mutations do tumor suppressors tend to get?

A

Recessive, so losing one could lead to inbalanced growth but need to lose both alleles to have an effect

26
Q

What type of mutations do proto-oncogenes tend to get?

A

Dominant mutations
-proto-onco can become oncogenes with only one mutated copy

27
Q

What checkpoint monitors are b/w G1 -S?

A

CHK2
ATM
p53
-check for damaged DNA

28
Q

What checkpoint monitors are in the S phase?

A

ATM
ATR
p53
-check for DNA damage and if the S phase is going well

29
Q

What checkpoint monitors are at G2?

A

p53
-check if genome duplicated and if the DNA is damaged

30
Q

What checkpoint monitors are at M phase?

A

Bub
Mad
-check if chromosomes condense and attached to the mitotic spindle

31
Q

What is the role of p53?

A

It’s just a monitor to see if things are going well and if the process should move forward. It does not have a role in doing anything in the cycle. In other words, the cycle can/will keep going even if p53 is deleted.

32
Q

What happens when DNA is damaged

A

checkpoint kinases detect damage, inhibit MDM2 (which normally targets p53 for degradation), so p53 increases, which ultimately inhibits S phase entry

33
Q

What is MDM2?

A

a proto-oncogene that can inhibit p53
-can ultimately activate S phase entry

34
Q

What is E2F?

A

A transcription factor/DNA-binding protein responsible for binding to and activating transcription of replication machinery parts, promoting S phase entry
-always present - can get rid of an inhibitor to accept an activator receptor

35
Q

What is Rb?

A

=retinoblastoma
-factor that inhibits E2F, a transcription factor that promotes cell cycle progression
-is a tumor suppressor
-when phosphorylated by a CDK, leaves E2F complex, gets ubiquinated to get degraded and E2F stays bound to same site on its own and is available for co-activators instead of co-repressors

36
Q

7 deadly sins committed by cancer cells

A
  1. evading apoptosis
  2. self-sufficiency in growth signals
  3. insensitivity to anti-growth signals
  4. inflammatory microenvironment
  5. tissue invasion & metastasis
  6. limitless replicative potential
  7. sustained angiogenesis
37
Q

How does apoptosis work?

A

p53 can activate transcription of Death Factor Receptor (cells are very sensitive to p53 signal) neighboring cells send signals (Death Signals like FasL) to help sound the alarm for cell to kill itself
-p53 can also activate Bax

38
Q

What is Bax?

A

A channel that binds to mitochondrial surface to allow cytochrome C to escape (it should be inside the mito, nowhere else)

39
Q

What is the role of cytochrome C in apoptosis?

A

When Bax is activated by p53, it moves to the mitochondrial surface and allows cytochrome C to exit the mitochondra. This turns into a signal to the cell to induce apoptosis via pathway with activation of apoptosome and caspases

40
Q

What can block Bax?

A

Bcl2
-acts as a plug for Bax channels so cytochrome C cannot get out of the mitochondria

41
Q

What is Bcl2?

A

“plug” for Bax channels when they’re on the mitochondria allowing cytochrome C to get out and initiate apoptosis
-if levels rise, inhibits Bax and cannot induce this pathway to apoptosis
-overexpressed in B cell lymphomas

42
Q

Extrinsic vs intrinsic pathway to apoptosis

A
  1. extrinsic pathway of apoptosis begins outside a cell, when conditions in the extracellular environment determine that a cell must die. Might be cytotoxic T cell bound to ligand like TNF activating Death signal receptor
  2. intrinsic pathway of apoptosis pathway begins when an injury occurs within the cell and the resulting stress activates the apoptotic pathway. Intracellular death signals can be loss of growth factor signal, cell injury, DNA damage, excess Ca2+ - all allow mitochondria to release cytochrome C
43
Q

What happens in the apoptosis pathway after p53 initates it?

A
  1. Death signal receptor is activated (activation level determined by p53)
  2. FADD (DD = death domain) is released from the death signal receptor
  3. FADD activates inactive procaspases (proteases in their inactive form) to become active caspase 8
  4. caspase 8 activates other procaspases, including execution procaspases
  5. execution capaspases destroy DNA and other cellular parts, making blebs (does not lyse…that would be inflammatory) w/ internal contents
  6. blebs go away in serum and get eaten by macrophages
  7. caspase 8 also activates Bad (Bid) that will displace Bcl2 from Bax channels and allow cytochrome c to exit
44
Q

What about p53 determines the fate of a cell after DNA damage?

A

the [p53]
- a DNA-binding protein
- a transcription factor
- recognizes specific sequences in genome and activates transcription of those genes that have the binding site upstream

45
Q

How is [p53] determined?

A

By MDM2

46
Q

Relationship b/w p53 and MDM2

A

P53 is the transcription factor that makes MDM2
-as [p53] increases, MDM2 degrades the p53 and an E3-E2 ubiquitin ligase
-both in low [] in the cell

47
Q

What is activated when there’s DNA damage and other stresses?

A

Chk2, ATM and other kinases
-they phosphorylate MDM2 so doesn’t fxn properly and it stops recognizing p53 -> p53 increases
-> transcribes more (including MDM2 even though it’s inactivated), p21, DNA repair factors, tumor suppressors (PTEN, INK4aARF)
-> p21 inhibits the cell cycle by inhibiting CDK and will make other tumor suppressors

48
Q

If DNA damage is really bad, what happens?

A

Chk2, ATM and other kinases are activated -> phosphorylate MDM2 -> p53 increases ->
1. transcribes p21, DNA repair factors, other tumor suppressors (PTEN, INK4aARF, etc) -> activates Cip21
2. transcribes Fas (death receptor), IGFBP (blocks survival factors) and Bax (pro-apoptotic factor)

49
Q

5 weird things about p53

A
  1. When it fails to do its job, it accumulates to high levels (if tp53 is mutated in a way that makes p53 fail, it accumulates)
  2. TP53 has mostly missense mutations (APC and other tumor suppressors have mostly null mutations. Proto-oncogenes more often have missense mutations)
  3. Misssense mutations in TP53 are dominant, but null mutations are recessive, so deletion of one copy of the gene is LESS detrimental than a point mutation
  4. **getting rid of a DNA damage checkpoint can make cells MORE RESISTANT to damage - like hormesis?
  5. most cancerous growths start w/ a dominant negative point mutation in TP53 but most tumors have 2 null mutations (progress over time)
50
Q

Why does p53 mutate more similarly to proto-oncogene mutations rather than like other tumor suppressors?

A

Most commonly have dominant missense mutations
-most mutations occur w/ in the sequence-specific DNA binding domain, which is what makes them dominant

51
Q

Why is the deletion of one copy of the TP53 gene LESS detrimental than a point mutation?

A

Because missense mutations are dominant and null mutations are recessive

52
Q

How is p53 regulated?

A

By stability of the protein, not at the level of transcription

53
Q

How does p53 fxn?

A

As a tetramer that binds DNA cooperatively
-unusual for a DNA-binding protein
-all 4 parts of the tetramer need to agree that they found their DNA sequence (which is also larger and more complex than typical DNA binding sequence)
-this is why a point mutation is so detrimental - one subunit will not be able to recognize its DNA binding sequence
-only 1/16 of the tetramers are lucky enough to get 4 good p53 subunits (by random probabilty) so only 1/16the are functional

54
Q

How does getting rid of a DNA damage checkpoint make cells MORE resistant to damage?

A

Deletion of p53 completely -> cells stay alive whereas norm cells die after high dose x-rays
-w/o the p53 checkpoint, DNA damage repair occurs less, apoptosis occurs less (unless necrotic) and cells will survive (like hormesis)
-Allows cells to live w/ DNA damage

55
Q

How is it that most cancerous growths start w/ a dominant negative point mutation in TP53 but most tumors have 2 null mutations in TP53?

A

Cancer cells evolve
-missesnse mutation in 1 allele is the start, takes p53 down to very low activity levels
-some cells still going under apoptosis
-> picks up a null or missesnse mutation in other allele over time, further decreasing p53 activity to «6%

MCC (44 decks)

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