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MCB2050 > Topic 5 > Flashcards

Topic 5 Flashcards

1
Q

Cancers arise when critical ____ that regulate ____ are _____.

A

critical genes that regulate cell cycle are mutated

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2
Q

What do mutations cause in the cell?

A

Cell proliferation - multiply

Impaired cell death - survive

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3
Q

Cancer mutations deregulate:

A
  • cell signalling (damage sensor)
  • cell cycle control (proliferation)
  • gene expression
  • cell death (apoptosis)
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4
Q

START checkpoint

A

-decision on whether to divide or not in the cell cycle (divide or apoptosis)

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5
Q

What are the key regulators of the cell cycle?

A

CDK - cyclin dependent kinases.

-very tight control between transitions to different phases

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6
Q

4 phases of cell cycle

A

G1, S, G2, M

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7
Q

Cyclin

A

regulatory protein that regulates CDK

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8
Q

Cyclin abundance (in order of cell cycle)

A 
G1:
Cyclin D
Cyclin E
S:
Cyclin A
G2: 
Cyclin B
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9
Q

CDK activity (in order of cell cycle)

A 
G1:
CDK4
CDK2
S:
CDK2
G2:
CDK1
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10
Q

CDKI

A

cyclin dependent inhibitor that can restrain cell cycle progress

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11
Q

When CDKs are activated by cyclins, what do they do?

A

Phosphorylate specific proteins that control cell cycle progression in temporal and cyclical pattern

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12
Q

How do CDKI (inhibitors work)?

A

-CDKI bind to the CDK to inactivate
or
-bind to the CDK/cyclin complex

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13
Q

Cell cycle checkpoints (definition)

A

control mechanisms that ensure cell cycle progression occurs appropriately

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14
Q

4 Cell Cycle Checkpoints

A 
G1:
G1/S Checkpoint
G2: 
DNA replication checkpoint
M:
Spindle assembly checkpoint
Chromosome segregation checkpoint
G1:
DNA damage checkpoint
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15
Q

Purpose of checkpoints:

A

to guard the genome from

  • loss of genetic info (unreplicated DNA, DNA damage, chromosome breakage)
  • missing or extra chromosomes (unattached chromosomes)
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16
Q

G1/S transition checkpoint

A
  • requires (dependent) nutrient/growth factors (–> cyclin D)
  • independent synthesis of cyclin E (late G1)
  • when G1/S checkpoint activated, CDK(2/4) - which are in in G1 - are inhibited (to prevent forward progression to S phase)
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17
Q

Spindle assembly checkpoint

A
  • abnormal spindle
  • cell cycle arrested
  • signal apoptosis machinery
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18
Q

DNA replication and DNA damage

A
  • excessive ssDNA (arrest or pertubation/change of replication forks)
  • dsDNA breakage
  • unfinished DNA repair

activation allows for:

  • arrest cell, repair damage, resume
  • nonrepairable, apoptosis
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19
Q

Apoptosis

A

molecular and morphological process to controlled cellular self destruction

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20
Q

3 steps of apoptosis

A
  1. reduction in nuclear size, condensation of chromatin at nuclear periphery, detachment from surrounding cells
  2. cell shrinkage, blebbing of cell membrane = apoptotic bodies
  3. phagocytosis by macrophage of apoptotic bodies
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21
Q

Excess apoptosis diseases

A
  • huntington’s
  • alzheimer’s
  • parkinson’s
  • traumatic brain injury
  • stroke
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22
Q

Inadequate apoptosis diseases

A
  • cancer
  • multiple sclerosis
  • diabetes
  • arthritis
  • systemic lupu erythematosus
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23
Q

Caspase

A
  • cysteinyl aspartate specific proteinase
  • cysteine proteases (active site cysteine) that cleave after aspartate
  • -present in inactive pro-form in healthy cells
  • degrade specific proteins that lead to cell death
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24
Q

Initator caspase

A

effector
-caspase 9 = stress
caspase 8 = death receptor

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25
Q

Effector caspase

A

executioner

  • cleave specific cellular proteins = inactivation
  • caspase 3, 6, 7
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26
Q

Adaptor proteins

A

bind to initiator caspases to activate

Apaf-1 & FADD

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27
Q

Caspase activation regulated by _____ proteins

A

BCL-2 family proteins

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28
Q

Pro-apoptotic Bax/Bak

A

induce apoptosis by producing channels that release cytochrome c from mitochondrial outer membrane

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29
Q

Cytochrome C

A

binds to adapter protein (Apaf-1) which oligomerizes apoptosome
-activates initiator caspase-9

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30
Q

Activated caspase-9

A

cleaves effector caspase 3

31
Q

Caspase 3

A

cleaves proteins leading to apoptotic body

32
Q

BCL-2

A

proSURVIVAL BCL-2 inhibits apoptosis

via preventing BAX/BAK oligomerization

33
Q

BH3-only proteins

A

proAPOPTOTIC inhibit proSURVIVAL BCL-2 and may directly activate BAX/BAK

34
Q

Oncogene

A

-normal function: promote cell survival or proliferation (proto-oncogene)
-hyperactive activator - no longer growth factor dependent
-over expression/mutation: cause cancer
due to point mutation, chromosomal translocation, amplification
-requires ONE mutation to enable oncogene to stimulate cell proliferation

35
Q

Proto-oncogene:

A

the normal counterpart to an oncogene – proper regulation

-promote cell division and cell survival

36
Q

Tumor suppressor genes

A

-normal function: inhibit cell survival or proliferation (division)
-loss of function mutation: cause cancer
due to deletion, point mutation, promoter methylation (deactivates)
-require TWO inactivating mutations to eliminate tumor supressor gene and stimulate cell proliferation

37
Q

Proto-oncogenes and tumor suppressor genes are ____ that regulate _____. Only when ___ do they ____

A

normal genes that regulate cell proliferation.

mutate induce cancer or fail to prevent progression.

38
Q

Examples of oncogenes

A

HER2
ras
c-myc
Bcr/Abl

39
Q

Examples of tumor suppressor genes

A

Rb

p53

40
Q

Overexpression/hyperactivity of oncogenes induce signalling pathways that are ______________

A
  • no longer growth factor dependent.
  • oncogenes directly controls expression of cyclin D
  • therefore GF independent
41
Q

c-ras

A

inactive ras / GDP
active ras / GTP
-ras is an oncogene

42
Q

Normal regulation of Ras protein

A
  • in the cytoplasm, extracellular signalling influences the state of ras (inactive/active)
  • activated by phosphorylation of GDP to GTP
  • active Ras transduces signal to nucleus to regulate transcription of genes involved in cell division
43
Q

Mutant Ras protein is _______

A

unregulated.

  • impaired control by growth factors
  • constitutively active
  • extracellular signal has NO influence on mutant Ras
  • mutant Ras = active state
  • signal to nucleus
  • lots of cell division genes transcribed
  • uncontrolled
44
Q

Main contributors to cancer signalling pathways: (4)

A
  • deregulation of growth factors
  • hyperactive ras, myc, jun, fos, src (oncogenes)
  • continuous grow/divide signal (constitutive)
  • G1/S checkpoint compromised
45
Q

Rb and p53 flow chart typically.

A 
Typically:
growth factors
regulates
cyclin D (G1 phase)
which inhibits
Rb (tumor supressor)
inhibitting E2F
(G1/S checkpoint also inhibits E2F)
allowing for 
cyclin E to regulate S phase

(DNA damage checkpoint inhibits)
p53
which initiates transcription of protein
p21 (CDKI)
which inhibits
CDK2/cyclin E/A complex (regulating S phase)

46
Q

Rb acts as a brake on ____ progression

A

G1/S phase progression.

47
Q

E2F

A

transcription factor that is inactivated by binding Rb.

Otherwise, it transcribes genes needed for S phase.

48
Q

What phosphorylates Rb? What does this do?

A

Growth factors stimulate cyclin D.
CDK4/cyclinD + CDK2/cyclinE phosphorylate Rb.
This prevents Rb to bind to E2F.
E2F can now transcribe genes for S phase.

49
Q

For S phase to progress what does the Rb and E2F look like.

A

Rb and E2F are not bound.
Rb is phosphorylated by CDK4/cyclinD and CDK2/cyclin E
E2F is free and active as a transcription factor..

50
Q

Tumor suppressor genes: ______- of mutant cell cycle inhibitor p53/Rb allows for cell proliferation

A

Loss of function or loss of expression. Without Rb E2F is free to follow through with transcription of S phase i.e. cyclin E

51
Q

Mutation in which 4 molecules can lead to cancer. (regarding tumor suppressor genes)

A

CycD
CycE
Rb
E2F

52
Q

p53 gene
mutation in __ of cancers
leads to___

A
  • mutation occurs in 50% of cancers

- leads to genome instability

53
Q

loss of p53 = genome instability

A
  • cells escape apoptosis and divide with damaged DNA

- these cells can accumulate MORE mutations which increase probability of tumor formation (two hit)

54
Q

what is p53?

A
  • transcription factor that upregulates apoptotic genes
  • i.e. BAX = caspase activation = cell death
  • typically p53 is activated if there is unreparable DNA damage (increase in p53)
55
Q

Name the processes that mutations in these genes affect in order: ras, Rb, p53/p21, p53/BAX

A
  • signal transduction pathway
  • checkpoint regulation (G1/S)
  • response to checkpoint to DNA damage
  • response or execution of apoptosis
56
Q

3 ways to turn proto-oncogene into oncogene?

A
  • deletion or point mutation in coding sequence (hyperactive protein)
  • gene amplification (overproduction of the normal protein)
  • chromosome rearrangement (nearby regulatory sequence causes overproduction or fusion to actively transcribed gene)
57
Q

Gene amplification of proto-oncogene to oncogene. 2 specific genes.

A

c-myc or HER2

Abnormal expression at abnormally elevated levels.

58
Q

C-myc

A

transcription factor that regulates G1/S transition

59
Q

HER2

A

receptor that activates MAPK signalling (proliferation)

60
Q

Chromosome rearrangement (proto-oncogene to oncogene). 2 specific chromosomes and disease associated with

A 
Philadelphia chromosome.
Fusion protein is hyperactive.
Chronic myelogenous leukemia.
Burkitt's lymphoma
Nearby regulatory sequence causes overproduction of c-myc protein.
61
Q

fusion protein bcr-abl

A

tyrosine kinase activity is now constituitively active

62
Q

Philadelphia chromosome

A
  • chromosome 9 and 22
  • reciprocal translocation produce philadelphia
  • fusion protein of bcr (from small chr22) and abl (from large chr9)
63
Q

Burkitt’s lymphoma

A
  • reciprocal translocation of chromosome 8 and 14
  • IGH immunoglobulin gene enhancer now controls c-myc (next to each other)
  • this causes the overproduction of c-myc
    note: c-myc control G1/S phase transition
64
Q

Knudson’s two hit hypothesis

A

appearance = single random mutation of familial tumors and need two random hits for sporadic tumors

Inherited bilateral retinoblastoma
(two eyes childhood tumor)
- high risk of 2 tumor
Sporadic unilateral retinoblastoma
-affects only one eye, no family history
-no further risk of 2 tumor
-rare somatic mutation of BOTH alleles
65
Q

Li-Fraumeni syndrome is caused by?

A

inherited p53 mutation (DOMINANT)
-p53 is signal that realizes DNA is damaged and will express genes that repair DNA or suppress cell cycle p21, and apoptosis BAX

66
Q

Cancers develop through accumulation of _______ in ____ and _____

A

accumulation of somatic mutations in proto-oncogenes and tumor supressor genes

67
Q

Six essential alterations for tumorigenesis

A
  1. self-sufficiency in growth signals
  2. Insensitivity to antigrowth signals
  3. Evasion of apoptosis
  4. Limitless replicative potential
  5. Tissue invasion and metastasis
  6. Sustained angiogenesis
68
Q

Self-sufficiency in growth signals

A
  • synthesize own growth factors
  • growth factor receptor over expressed
  • alteration in signal transduction
  • over expression of transcription factors
  • express mutant transcription factors
69
Q

Insensitivity to antigrowth signals

A

TGFb distruption

  • downregulation of TGFb receptors
  • express mutant receptors
  • mutations in SMAD4

TGFb inhibits G1/S progression

  • inhibits Rb phosphorylation
  • inhibits c-myc expression
  • increase CDKI
70
Q

Limitless replicative potential

A
  • immortalize
  • loss of p53
  • inhibit Rb
  • telomerase expression is overexpressed in cancer via end to end fusion
71
Q

Sustained angiogenesis

A
  • encourage blood vessel growth to provide O2 and nutrients

- secrete endothelial growth factors

72
Q

Tissue invasion and metastasis

A

-protease secretion
-altered expression of matrix binding proteins
-escape immune killing cells
tissue invasion, intravasation, survival in blood, extravasation, colonization

73
Q

Evasion of apoptosis

A

-inactivate pro-apoptotic genes (FasR)

activate anti-apoptotic protein genes (Bcl-2)

MCB2050 (10 decks)

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