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Biology 465 > Lecture 5 - 7 > Flashcards

Lecture 5 - 7 Flashcards

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1
Q

How do tyrosine kinases function?

A

They signal through modular protein-protein interactions

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2
Q

What are seven mechanisms that results in insensitivity to antigrowth signals?

A
  1. down regulation of TGF-Beta receptors (tumour suppressor)
  2. expression of mutant receptors
  3. deletions in Smad 4 (tumour suppressor)
  4. deletions of Ink4A/B
  5. mutations in CDK4 render it unresponsive to Ink4A/B
  6. loss of Rb/inactivation of Rb
  7. blocking terminal differentiation signals
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3
Q

What mutations can occur during the steps of the TGF-Beta pathway?

A
  1. loss-of-function mutations in receptors block TGF-Beta signal
  2. loss-of-function mutations in Smads block TGF-Beta signal
  3. decreased production of p15 or Ink4a/b increases proliferation
  4. decreased production of PAI-1 allows
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4
Q

What is the role of Smad3 and Smad4?

A

Smad3 is activated through phosphorylation by a Type 1 receptor. Active Smad3-P activates free floating Smad4. Smad4 enters the nucleus and promotes the transcription of p15 and PAI-1.

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5
Q

What does p15 do?

A

It is a cell cycle inhibitor

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6
Q

What does PAI-1 do?

A

It is an inhibitor of protease that degrades extracellular matrix proteins.

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7
Q

What is Ink4a/b?

A
  • a family of cyclin-dependent kinase inhibitors (CKIs).

- the members of this family (p16INK4a, p15INK4b, p18INK4c, p19INK4d) are inhibitors of CDK4, as well as CDK6.

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8
Q

What is the mechanism of overexpression of CycD in cancer cells?

A
  1. Loss of Ink2’s or Rb
  2. Mutation in CDK4 can’t interact with p16
  3. Overexpression
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9
Q

How is E2F activated as the transcription factor of proteins needed for DNA synthesis?

A

When bound to CycD and CDK4, p16 inhibits the kinase. Once unbound, the kinase complex phosphorylates Rb, which is bound to E2F, and releases it.

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10
Q

What does Rb/E2F do?

A

It is a repressor of transcription of proteins required for DNA synthesis.

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11
Q

How does TGF-Beta effect Ink4a/b?

A

It positively regulates Ink4a/b production

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12
Q

What are the three stages of cancer immunoediting?

A
  1. Elimination
  2. Equilibrium
  3. Escape
    - increases from genetic stability/tumour heterogeneity
    - increase in immune selection
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13
Q

What is the elimination stage in cancer immunoediting?

A

The immune system attacks the antigen or the unusual cells. It is constantly occurring and rapid.

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14
Q

What is the equilibrium stage in cancer immunoediting?

A

An asymptomatic (non-harming), long phase. The unusual cells are persisting but not being resolved. The unusual cells typically have a mutation that makes it invisible to the immune system.

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15
Q

What is the escape stage in cancer immunoediting?

A

The cancer cells divide enough to break through the basement membrane.

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16
Q

How does Fas induce apoptosis?

A

Fas binds to the Fas receptor, death receptor signaling. FaR trimerizes with Fadd and ProCaspase 8 which results in apoptosis.

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17
Q

How can cancer evade apoptosis?

A

Due to genetics, environment and sometimes evolution.

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18
Q

What happens to the pathways when it is noticed by the cell that there is a problem with the plasma membrane?

A

The pathways that result to apoptosis will be turned on but some of the receptors may not be expressed.

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19
Q

What are 5 mechanisms that cancer cells use to evade apoptosis?

A
  1. growth factor activation of PI3 kinase pathway
  2. inactivation of PTEN (tumour suppressor)
  3. inactivation of p53 (tumour suppressor)
  4. downregulation, inhibition or mutations in proapoptotic proteins
  5. overexpression of anti-apoptotic proteins (ie. Bcl2 (oncogene))e
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20
Q

What occurs in the absence of trophic factors (growth factors)?

A
  • Caspase activation
  • Bad is bound to Bcl-2
  • Bax causes the membrane to be leaky and release ions
  • Cyt c binds to Apaf 1 which activates Procaspase 9
  • now activated caspase 9 activates procaspase 3
  • procaspase 3 cleaves substrates that leads to cell death
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21
Q

What occurs in the presence of trophic factors?

A
  • inhibition of caspase activation
  • the trophic factor binds which activates PI-3 (prevents the activation of Procaspase 3)
  • Akt kinase is then activated and phosphorylates Bad with ATP
  • phosphorylated Bad binds to 14-3-3
  • the lack of Bad binding to Bcl-2, Bcl-2 inhibits Bax
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22
Q

How does the activation of GF pathway lead to PI3 kinase activation in two ways?

A
  1. Ras can activate PI3kinase and pro-survival
  2. Recruitment to the membrane
    - shuts down the apoptotic pathways to grow
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23
Q

What is the role of lipid kinases?

A

They create docking sites for downstream signaling molecules (phosphatidyl-inositol (PI))

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24
Q

What is PIP3?

A
  • Phosphatidyl-inositol (3,4,5) triphosphate (PIP3)

- it recruits and activates Akt/PKB (binds to the phosphorylated 3,4 and 5 positions on PIP3)

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25
Q

How is PIP3 phosphoryolated and dephosphorylated?

A
  • phosphorylated by PI3K

- dephosphorylated PTEN (tumour suppressor)

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26
Q

How is Akt/PKB activated?

A

It is phosphorylated by PDK1, PKD2

27
Q

What is the role of Akt?

A
  • It controls growth proliferation angiogenesis and survival

- activated by phosphorylation with ATP

28
Q

How does activated Akt/PKB effect GSK-3Beta, HIF-1alpha and Bad?

A
  • it inhibits GSK-3Beta by phosphorylation to inhibit proliferation
  • it phosphorylates HIF-1alpha to allow the cell to undergo angiogenesis
  • it inhibits Bad via phosphorylation to inhibit apoptosis
29
Q

How is PTEN important as a tumour suppressor?

A

During tumor development, mutations and deletions of PTEN occur that inactivate its enzymatic activity leading to increased cell proliferation and reduced cell deat

30
Q

What are the roles of p53?

A
  1. Growth arrest
  2. DNA repair
  3. Apoptosis
31
Q

Which oncoproteins bind to p53 and inhibit its function?

A
  • SV40 Large T
  • E1B adenovirus
  • E6 papilloma virus
32
Q

Which six problems result in the activation of p53?

A
  • lack of nucleotides
  • UV radiation
  • ionizing radiation
  • oncogene signalling
  • hypoxia
  • blockage of transcription
33
Q

How does p53 (“The Guardian of the Genome”) protect the cell?

A
  • cell cycle arrest
    • > senescence
    • > return to proliferation
  • DNA repair
  • blocks angiogenesis
  • apoptosis
  • conserves the genome by preventing proliferation that could lead to a genome
34
Q

How is p53 levels, in a cell, controlled?

A
  • usually the levels do not build up in the cell as high levels are a problem
  • it is degraded by ubiquitin proteasome system when not needed
  • DNA damage stabilizes p53
  • > p53 is a negative regulator of growth
35
Q

What happens to p53 and Mdm2 when there is DNA damage in the cell?

A
  • Mdm2 is inactivated (phosphorylated in its binding site)
  • Chk2, ATm or ATR phosphorylates p53 which becomes active
  • becomes a transcription factor for mdm2 and other target genes
  • mitogenic and cell survival signals bind to mdm2 DNA to assist in the expression
36
Q

What happens to p53 and Mdm2 when there are cell survival signals?

A
  • free floating Mdm2 is activated by Akt/PKB (not phosphorylated in its binding site)
  • Mdm2 is able to bind p53
  • results in p53 being ubiquinated and digested by the cytoplasmic proteasome
37
Q

How is p53 negatively regulated?

A

p53 binds to the Mdm2 gene and expression occurs. Mdm2 binds p53 to cause its ubiquination.

38
Q

Explain the p53/Mdm2 complex when DNA is damage and when DNA is repaired.

A

DNA damage -> ATM Kinase activated -> no complex -> p53 increases -> Mdm2 increases
DNA repaired -> ATM Kinase inactivated -> MDm2 binds p53 -> p53 decreases

39
Q

Which category of genes does p53 control?

A
  • growth arrest genes

- apoptosis genes

40
Q

What is p21?

A
  • also known at waf1
  • inhibits Cdk 2 (no S phase) and Cdc2 (no M phase)
  • with it comes an increase in Bax
41
Q

What is GADD45?

A
  • growth arrest and DNA damage protein
  • increases in amounts with other stress proteins (eg., p21)
  • inhibits Cdc2 so no M phase
42
Q

What is 14-3-3 sigma?

A
  • sigma protein

- inhibits Cdc2 so no M phase

43
Q

What is Bax and Apaf1?

A
  • p53 binds and expresses Bax and Apaf1
  • Bax induces the release of cytochrome c, which binds to procaspase 9
  • Apaf1 (always near the mitochrondrial membrane) also binds to procaspase 9 and it becomes caspase 9
  • results in apoptosis
44
Q

What is the role of p14 Arf?

A
  • It stabilizes p53 by sequestering Mdm2
  • it’s a tumour suppressor
  • prevents Mdm2 from binding p53 at times of DNA damage
45
Q

Which antiapoptotic protein is overexpressed in a cancer cell to evade apoptosis?

A
  • Bcl-2 (pro survival)
    • oncogene
  • controls the permeability of the mitochondrial membrane to cytochrome C
46
Q

Which proapoptotic proteins are downregulated or inhibited in a cancer cell to evade apoptosis?

A
  • Bax subfamily (pro-apoptotic)
  • BH3-only (pro-apoptotic)
  • Bad, Bid (pro-apoptotic)
  • controls the permeability of the mitochondrial membrane to cytochrome C
47
Q

How are Fasf and Apaf1 related?

A
  • both lead to the activation of caspase 3
    • Fasf -> caspase 8
    • Apaf1 -> caspase 9
  • independent activations
  • Fasf is extrinsic and Apaf1 is intrinsic
  • crosstalk is provided by Bid (BH3-only protein)
48
Q

How do regular cells and cancer cells differ in terms of replication?

A

Normal cells: have a finite replicative potential (60-70 doublings)
Cancer cells: have infinite replicative potential

49
Q

Why is truncated Bid important?

A
  • Active caspase 8 cleaves cytosolic Bid, which results in truncated Bid.
  • t-Bid induces Bax/Bak which results in the leakiness of the mitochondria.
  • Release of cytochrome C
50
Q

What is senescence?

A

The condition or process of deterioration with age (phase 3)

51
Q

If grown in culture, what are the three phases of growth?

A

Phase I: little to no growth
Phase II: The phase where most of the growth occurs
Phase III: Senescence

52
Q

What is the proliferation of cells limited by?

A

The length of telomeres of chromosomes

  • reaches a very short telomere
  • cell enters crisis
  • apoptosis
53
Q

How much telomeric DNA is loss from chromosomes during each cell cycle?

A

50-100bp

54
Q

What is the danger of a cell in crisis?

A
  • DNA recombination is not very efficient
  • there is an increased risk of mutation
  • especially in hTERT (human telomerase reverse transcriptase)
55
Q

Why is tumour promoting inflammation a problem?

A
  • don’t want to over response of the immune system
56
Q

What is the difference between chronic and acute?

A

Acute: There is resolution of the stress and the number of cells in the area decreases
Chronic: The stress is not resolved. Cytokines contribute to the genomic instability. Some chronic inflammatory diseases are associated with cancer.

57
Q

What are the two mechanisms of angiogenesis?

A
  • Increase the expression of proangiogenic factors (VEGF)

- Decrease the expression of antiangiogenic factors (Thrombospondin)

58
Q

How does Ras effect VEGF?

A

Ras activation can lead to VEGF expression in some cells

59
Q

How does p53 effect Thrombospondin?

A

Loss of p53 can contribute to loss of Thrombospondin

60
Q

What is angiogenesis?

A

The ability for cells to get required oxygen by creating new blood vessels to prevent becoming necrotic.

61
Q

What is released when cells become hypoxic?

A

HIF1-alpha

62
Q

If there is no DNA damage, what happens to p53 and Mdm2?

A
  • Mdm2 is expressed due to excess p53 binding to the gene (due to mitogenic and cell survival signals)
  • p53 is unphosphorylated but Mdm2 is phosphorylated which results in ubiquitin mediated degradation of p53
63
Q

What occurs to p53 and Mdm2 when there is DNA damage?

A
  • ATM kinase is activated which phosphorylates both p53 and Mdm2 (in binding site)
  • no p53/Mdm2 complex so p53 and Mdm2 levels increase
64
Q

What occurs to p53, ATM and Mdm2 when DNA is repaired?

A
  • ATM kinase is inactivated which allows Mdm2 to bind to p53

- p53 levels decrease due to ubiquination

Biology 465 (15 decks)

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