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MCM Test 2 > Cell Cycle, Apoptosis and Cancer > Flashcards

Cell Cycle, Apoptosis and Cancer Flashcards

1
Q

2 main phases of the cell cycle

A
  1. Interphase–> growth of the cell. Made up for G1, S, G0 and G2
  2. Mitosis–> cell division
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2
Q

What main phase do cells spend most of their time in?

A

Interphase

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3
Q

G1 phase

A

RNA and proteins synthesis occur
Cell growth
Takes 4 hours

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4
Q

S phase

A
  1. Replication: DNA is replicated to form homologs. Each chromatid now has a sister chromatid that is connected by a centromere (a chromosome).
  2. Histone synthesis

The S phase takes 8 hours.

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5
Q

What is the order of phases

A

G1/G0–>S–>G2–>Mphase

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6
Q

Mitosis consists of what two important steps

A 
Nuclear division (which occurs at the beginning) 
&
Cell division (cytokinesis) at the end
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7
Q

Cytokinesis

A

Cell division

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8
Q

G2

A

Preparation for mitosis occurs.

Takes 12 hours.

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9
Q

G0 phase

A

Cells enter the G0 phase as a result of poor nutrient/environmental conditions. Thus, they withdraw from the cycle.

Different types of cells end here: neurons, cardiac muscles and RBCs

No cell growth or division occurs here.

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10
Q

Summary of length of time G1, S and G2 phase take

A

G1- 4 hours
S- 8 hours
G2- 12 hours

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11
Q

What are the stages of the cell cycle where errors are checked?

A

There is 1 restriction points

3 checkpoints (G1 checkpoint, G2 checkpoint and metaphase checkpoint).

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12
Q

What occurs at the restriction point?

A

Restriction point occurs 2 hours before the S phase.

If growth factors are not present, restriction occurs and the cell is transferred to G0.

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13
Q

When exiting from the Restriction Point, are growth factors needed?

A

No. Exit from the Restriction Point does NOT require growth factors.

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14
Q

G1 Checkpoint

A

The G1 checkpoint occurs right after the restriction point.

Here, we examine DNA to make sure it is free of damage before replication occurs.

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15
Q

G2 Checkpoint

A

Occurs to see if any errors in DNA replication occurred.

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16
Q

Metaphase Checkpoint

A

Ensure that the chromosomes are attached to the mitotic spindle and aligned correctly

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17
Q

What activates the cell cycle?

A

Growth factors

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18
Q

What alters the cell cycle?

A

Cell signaling

Cell signaling can lead to

  1. Apoptosis
  2. Proliferation
  3. Differentiation

The interplay in between cell signals is what keeps the cell cycle in check.

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19
Q

How can the G1 checkpoint be regulated?

A

G1 Checkpoint can be regulated by the binding of Mitogen.

Mitogen is a growth factor.
1. When it binds to a mitogen receptor, it acts through a RAS pathway to initiated an intracellular cascade of events.

  1. Mitogen will activate [Myc], a transcription factor that drives cell proliferation.
  2. [Myc] increases G1-cyclin dependent kinase (CDK) levels.
  3. G1-CDK will phosphorylate Retinoblastima (Rb).
  4. Phospho-Rb will release sequestered E2F
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20
Q

What does E2F do?

A

E2F drives cells from G1–> S phase.

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21
Q

How does retinoblastima (Rb) and cyclin work together?

A

When not phosphorylated, Rb sequesters E2F so that it will not bind to DNA. Thus, we cannot proceed to S phase.

Remember we said that E2F drives cells from G1 to S phase.

When Rb is phosphorylated, it releases E2F into the nucleus so that the cell can proceed to the S phase.

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22
Q

What drives cells from G1–>S phase of the cell cycle?

A

When Rb is phosphorylated, it releases the sequestered E2F and thus, activating it.

Thus, the cell can now divide :)

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23
Q

In non-dividing cells (neurons, cardiac muscle, RBC), is Rb phosphorylated or no?

A

Rb is not phosphorylated, which causes the sequester of E2F.

Ex. in neurons, cardiac muscles, heart; retinoblastoma will not be phosphorylated

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24
Q

What is the heart of the cell-cycle control system?

A

The heart of the cell-cycle control system is the

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25
Q

What are cyclins?

A

Cyclins are proteins that interact with CDK and regulate their activity.

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26
Q

When is CDK active?

A

CDK (cyclin-dependent kinase) are only active when cyclin is present.

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27
Q

Does cyclin expression remain the same throughout the cell cycle?

A

No, cyclin expression rises and falls, causing kinase activity to rise and fall as well.

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28
Q

What does a cyclin-CDK complex do?

A

[Cyclin-CDK complexes] regulate cell cycle events.

When CDK is activated with cyclin, it activates its kinase activity.

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29
Q

When cyclin binds to CDK, is it fully activated?

A

No. To fully activate a cyclin-CDK complex, we need

CAK (CDK-activating kinase). CAK will phosphorylate the the complex at the CAVE site and activate it :)

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30
Q

What are inhibitors of the fully activated cyclin-CDK complex?

A
  1. WEE1 kinase
  2. p27

[WEE1 Kinase and P27] are both CDK inhibitors.

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31
Q

WEE1 Kinase

A

WEE1 Kinase is a CDK inhibitor.
It will phosphorylate the cyclin-CDK complex again (because CAK phosphorylates it to active it). Phosphorylation a second time inactivates it.

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32
Q

What is the mechanism of activation of CDK?

A

Without cyclin bound,

  • CDK has a T loop that blocks its active site.
  • When cyclin binds, the T loop moves out of the active site, activating the [cyclin-CDK complex].

-CAK will then come in and phosphorylate the T-loop, fully activating the cyclin-CDK complex!

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33
Q

Which cyclin complexes help the cells pass through the restriction point in late G1 phase?

A

Cyclin D-CDK4

Cyclin D-CDK6

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34
Q

How can cyclin-CDK complexes be regulated?

A
  1. Phosphorylation.
    ex. WEE1 Kinase, CDC25 Phosphotase
  2. CKI (cyclin kinase inhibitors)
    ex. P27
  3. Proteolysis of cyclin by a proteosome
    ex. APC
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35
Q

How is CDK activity primarily determined?

A

By the rise and fall of cyclin levels

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36
Q

Phosphorylation regulation of cyclin-CDK complexes

A

Cyclin-CDK complexes are fully active when CAK (CDK activating kinase) activates the cave site of CDK.

However; WEE1 Kinase is an enzyme that phosphorylates the ROOF site of CDK, inactivating the CDK activity.

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37
Q

As we have discussed, WEE1 Kinase will phosphorylate the roof site of CDK, inactivating the complex. Can we reverse this?

A

Yes. We can reverse this using [CDC25 phosphotase]. This will dephosphorylate the roof site and increase CDK activity.

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38
Q

CKI and cyclin-CDK activity

A

P27 is a CKI.

P27 will bind to the complex and inactivate it. P27 regulates early cell events (G1–>S phase).

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39
Q

As we have discussed, cyclin levels vary throughout the cell cycle and thus, regulate the levels of active CDK. What causes cyclin levels to drop as we go from metaphase–> anaphase?

A

Cyclin turnover is regulated by a signal-dependent protein degradation via anaphase-promoting complex (APC also called cyclosome).

APC is really important to progress from metaphase–> anaphase.

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40
Q

What is APC?

A

APC is a ubquitin ligase that is about 11-13 subunits.

APC is anaphase-promoting complex (aka cyclosome). It is responsible for decreasing levels of cylin M and S so that we can go from metaphase–> anaphase.

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41
Q

What is ubiquitin?

A

Ubiquitin is a protein that attaches to LYSINE residues on target and tags for degradation by a proteosome.

its a small 76 AA protein that exists in all eukaryotic cells.

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42
Q

What exactly does APC do?

A

[Anaphase promoting complex] is responsible for cyclin turnover, thus, it decreases levels of cyclin S and cyclin M to allow us to go from metaphase–> anaphase.

APC will ubiquitinize cyclin, marking it for degradation by a proteosome, decreasing levels. By decreasing cyclin, it decreases levels of CDK as well.

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43
Q

Method APC/ and Uquitination

A

APC is a ubiquitination ligase.

  1. APC will ubiquitinize cyclin M and S
  2. Now tagged for degradation by a proteosome
  3. Cyclin is degraded and CDK is de-phosphorylated.
44
Q

What must be degraded before we can move from metaphase–> anaphase?

A

Cyclin S and cyclin M must tagged for degradation by APC (anaphase progression complex) and destroyed by a proteosome.

45
Q

What are the levels of Cyclin going from metaphase–> anaphase?

A

Low because cyclin M and cyclin S levels must drop!

46
Q

What is p53?

A

p53 is like an alarm.

p53 is a tumor-supressor gene (transcription factor) that helps to regulate the cell cycle. Most of the time, p53 is inactive. However, when damaged DNA is detected, p53 sends a signal to the cell to undergo apoptosis.

47
Q

What is p53 called?

A

guardian of the genome

48
Q

In quiet cells that are not damaged, what is the status of p53?

A

If quiet cells that are not damaged, p53 is kept inactive by E3 Ubiquitin Ligase (MDM2).

49
Q

If DNA is damaged, how does p53 send a signal.

A

Remember, p53 is usually kept inactive by [E3 Ubiquitin Ligase] (MDM2)

  1. When damaged DNA is detected, it activates protein kinases.
  2. p53 is phosphorylated and MDM2 becomes inactive.
  3. p53 will lead to increased transcription of p21
  4. p21 will then bind and inactivate [cyclin-CDK complexes] to cause cell cycle arrest
50
Q

A big target for p53 is _______.

A

p21.

51
Q

What does p21 do?

A

When DNA is damaged, p53 will send a signal to p21.

Transcription of p21 increases and it inactivates [cyclin-CDK complexes], stopping the cell cycle and prevent replication of damaged DNA by decreasing CDK activity.

52
Q

Many cancers are a result of problems with ____

A

p53

53
Q

p21 is a _______________

A

CKI

Cyclin-dependent kinase inhibitor: binds and inactivates [cyclin-CDK complex] and causes cell cycle to STOP.

54
Q

What is CAK stand for

A

CDK-activating kinase

55
Q

What is apoptosis?

A

Programmed cell death

56
Q

Apoptosis can occur in 2 pathways. What are they?

A

Apoptosis can occur in 2 pathways

  1. Extrinsic (death receptor) pathway
  2. Intrinsic (mitocondrial) pathway

However, both pathways converge via the use of caspases.

57
Q

Internal stimuli that can cause apoptosis

A

abnormalities in the DNA

58
Q

external stimuli that can cause apoptosis

A
  1. removal of survival factors

2. proteins of tumor necrosis factor family (TNF)

59
Q

Intrinsic pathway of apoptosis

A

Intrinsic pathway of apoptosis is dependent on the mitochondrial.

It occurs in response to: damaged DNA,
lack of oxygen, lack of nutrients, lack extracellular surviving signals (mT dysfunction)

60
Q

What are the key regulators of extracellular survival signals?

A

BAX/BCL-2

61
Q

Extrinsic pathway is mitochondrial- dependent/independent

A

independent

62
Q

Apoptosis occurs through the use of ______

A

caspases

63
Q

Apoptosis is a intracellular/extracellular proteolytic cascade that is mediated by _______

A

INTRACELLULAR

mediated by caspases

64
Q

How are caspases first synthesized?

A

Caspases are proteases.

They are first made in their inactive form, procaspase and then activated by protease cleavage.

65
Q

When activated, what do caspases look like?

A

When activated, the large and small subunits of caspases form a heterodimer.

66
Q

There are 2 classes of caspases; what are they?

A
  1. initiators: caspase-8 and caspase-9. Help to activate the executioners
  2. Executioners: caspase 3: destroys the target and executes apoptosis
67
Q

Caspase initiators

A

Caspase-8

Caspase-9

68
Q

Caspase executioners

A

Caspase-3

They’re the ones to kill the target

69
Q

BCL-2 family proteins

A

Heavily regulate apoptosis. Some of them are anti-apoptosis and others are pro-apoptosis

70
Q

What is BAX?

A

BAX is a apoptosis regulator that is a part of the BCL-2 family. It is pro-apoptotic

71
Q

How does BAX work?

A

When there is no intrinsic death signal, BAX is a protein that is distributes throughout the membrane.

When an apoptic signal arrives, it causes pores in the mitochondrial membrane and cytochrome C and other proteins to leaks out to activate the apoptotic pathway!

72
Q

Intrinsic apoptotic pathway

A
  1. Proapoptotic signals (p53, BAX, BAK) are activated in response to extrinsic factors or DNA damage.
  2. Cytochome C is released from the mT.
  3. Cytochrome C interacts with [APAF-1] and creates an [apoptosome]
    * **Ca2+ is also released from the sER.
  4. Apoptosome will cause [procaspase 9–. caspace9]
  5. caspace 9 will activate EXECUTIONERS: caspase 3, 6 and 7.

BOOM: APOPTOSIS.

73
Q

What is APAF-1

A

APAF-1 is part of the intrinsic pathway of apoptosis.

It has a CARD domain and when it binds to cytochrome C, it cases the assembly of an apoptosome

74
Q

Apoptosome is called what?

A

WHEEL OF DEATH

75
Q

What decides: APOPTOSIS or PROLIFERATION?

A

BCL2 Family

Remember there are pro-aptosis fam members and anti-aptosis fam members

76
Q

Proto-oncogenes are normal or not normal?

A

Proto-oncogenes are NORMAL genes.

77
Q

What do proto-oncogenes express?

A
  1. growth factors
  2. receptors for growth factors and hormones
  3. transcription factors
  4. signal transducers

These all lead to cell grown and division

78
Q

What to oncogenes express?

A
  1. increased expression of protein products

2. altered proteins that do not respond to normal signals

79
Q

How do proto-oncogenes become oncogenes?

A

protooncogenes become oncogenes when they get a gain of function mutation

80
Q

Gain of function mutations

A
  1. point mutation
  2. deletion
  3. gene amplification
  4. translocation of chromosome
81
Q

What is an example of a oncogene and its expression?

A

HER2 receptor is a proto-oncogene.

However, a point mutation occurs that switches Val–> Glu and creates NEU.

This mutations causes receptors to dimerize and continued tyrosine kinase activity, even when there is no ligand.

It is responsible for breast cancer

82
Q

HER2 receptor–> NEU via?

What cancer does this cause?

A

HER2 receptor–> NEU due to a point mutation that changes Val–> Glu.

Receptors dimerize and tyrosine kinase activity is continued despite a ligand not being bound.

This is responsible for breast cancer!

83
Q

What happens when there is a deletion in the EGF receptor?

A

A deletion in the [EGF receptor]–> EGFRvIII.

Tyrosine kinase activity is prolonged.

Results in glioblastomas

84
Q

What results in glioblastomas

A

Glioblastomas can occur when there is a deletion in EGF receptor that causes it to become EGFRvIII.

As a result, tyrosine kinase activity is prolonged.

85
Q

BCR-ABL translocation creates what

A

BCR-ABL fusion oncogene and results in chronic mylogenous leukemia

86
Q

What happens when HER2 undergoes gene amplification?

A

it can result in the overexpression of HER2, which is common in a lot of breast cancers.

87
Q

What is a tumor supressor?

A

Tumor suppressors want to stop unnecessary cell growth and division.

  • triggers apoptosis
  • it couples DNA damage to the cell cycle by preventing it from happening
  • They can be DNA repair proteins
88
Q

Example of a tumor supressor

A

Retinoblastoma (Rb) is a tumor supressor.

It acts by sequestering E2F, a transcription factor that allows G1–>S phase.

89
Q

What is the heriditary form of Rb?

A

In the heriditary form of Rb says that if there is a mutation of 1 copy of Rb, you are heterozygous and your cells are predisposed to get the cancer.

A second hit must occurs on the other copy, increase chance of getting the cancer in both eyes and the tumor forms in tissues.

In order for a particular Rb cell to become cancerous, both of the cell’s tumor suppressor genes must be mutated. Thus, a second hit is required to get the cancer.

90
Q

Sporadic form of Retinoblastoma

A

The sporadic form of Rb is non-heritable. The non-cancerous cells are fine. There is no mutation of RB1. Thus, you have not received any predisposed mutations.

In the sporadic form, a cancerous cell will have to have to have 2 independent mutations. This is RARE.

Results in only getting cancer in one eye.

91
Q

What represses cell cycle progression of cancerous cells?

A

Tumor supressors

92
Q

What is BRCA?

A

BRCA is a tumor supressor that is a DNA repair protein. When there is a problem wit BRCA, it leads to decreased DNA repair and increased inactivation of tumor suppressors.

Inactivation of tumor supressors activate oncogenes.

93
Q

More examples of tumor supressor cells

A
  1. RB1
  2. TP53 (p53)
  3. PTEN (phophotase and tensin homolog)
  4. APC (adenomatous polyposis coli)
94
Q

A mutation in _____ is responsible for 70% of prostate cancers

A

PTEN ( tumor supressor cell)

95
Q

what kind of protein is p53?

A

tumor supressor.

its an alarm.

96
Q

What are metastasis suppressors?

A

Metastasis suppressors are cell adhesion proteins that prevent tumors from metastasizing. They block loss of contact inhibition.

97
Q

Multi-hit progression model of cancer says that:

A

to get cancer, you must get multiple hits over multiple times

98
Q

What is the progression in mult-hit model?

A

1st hit–> loss of APC

2nd hit–> Activation of RAS

3rd hit–> Loss of a tumor suppressor cell

4th hit–> loss of p53 activity

5th hit–> other alterations

then BOOM! DEATH!

99
Q

6 hall marks of cancer

A
  1. ability to grow alone
  2. do not respond to growth suppressors
  3. Invade and metasize
  4. Up-regulation of telomeroase activity (giving it immortaility)
  5. Angiogenesis ( secrete factors that allow blood vessor to form near the tumor: FEED ITS)
  6. Resisting cell death from apoptosis
100
Q

What is a viral oncogene

A

Virus takes over cells genome and takes up some proto-oncogene

Proto-oncogene could then mutate into an oncogene and then it would infect other cells

101
Q

How is HPV transmitted?

A
  1. E6 binds to p53, causing p53 to be degraded. Thus, loss of tumor suppression by p53.
  2. E7 binds to Rb, releasing E2F, allowing the cell cycle to go.
102
Q

There are many types of chemotherapeutic agents.

What do
alkylating agents and
antimetabolites do?

A

Alkylating agents affect all phases of the cycle by blocking DNA replication

Antimetabolites (ENZYMES) inhibit the enzymes that are involved in DNA synthesis

103
Q

There are many types of chemotherapeutic agents.

What do topoisomerase I and II inhibitors do?

A

Topo I inhibitors- inhibit TOPO1, an enzyme that resolves tangles in S phase

Topo II inhibitors result in tangled DNA in G2 phase

104
Q

There are many types of chemotherapeutic agents.

What do cytotoxic antibiotics do?

A

Cytotoxic antibiotics get in between bases in DNA and prevent synthesis

105
Q

Mitotic inhibitors

A

arrest cells in mitosis DURING METAPHASE

106
Q

What do cytotoxic antibiotics do compared to mitotic inhibitors?

A

Cytotoxic inhibitors will intercalate in between DNA bases to prevent the synthesis

Mitotic inhibitors will arrest mitosis in metaphase

MCM Test 2 (12 decks)

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