Topic 5 Flashcards
(73 cards)
1
Q
Cancers arise when critical ____ that regulate ____ are _____.
A
critical genes that regulate cell cycle are mutated
2
Q
What do mutations cause in the cell?
A
Cell proliferation - multiply
Impaired cell death - survive
3
Q
Cancer mutations deregulate:
A
- cell signalling (damage sensor)
- cell cycle control (proliferation)
- gene expression
- cell death (apoptosis)
4
Q
START checkpoint
A
-decision on whether to divide or not in the cell cycle (divide or apoptosis)
5
Q
What are the key regulators of the cell cycle?
A
CDK - cyclin dependent kinases.
-very tight control between transitions to different phases
6
Q
4 phases of cell cycle
A
G1, S, G2, M
7
Q
Cyclin
A
regulatory protein that regulates CDK
8
Q
Cyclin abundance (in order of cell cycle)
A
G1: Cyclin D Cyclin E S: Cyclin A G2: Cyclin B
9
Q
CDK activity (in order of cell cycle)
A
G1: CDK4 CDK2 S: CDK2 G2: CDK1
10
Q
CDKI
A
cyclin dependent inhibitor that can restrain cell cycle progress
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
12
Q
How do CDKI (inhibitors work)?
A
-CDKI bind to the CDK to inactivate
or
-bind to the CDK/cyclin complex
13
Q
Cell cycle checkpoints (definition)
A
control mechanisms that ensure cell cycle progression occurs appropriately
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
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)
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)
17
Q
Spindle assembly checkpoint
A
- abnormal spindle
- cell cycle arrested
- signal apoptosis machinery
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
19
Q
Apoptosis
A
molecular and morphological process to controlled cellular self destruction
20
Q
3 steps of apoptosis
A
- reduction in nuclear size, condensation of chromatin at nuclear periphery, detachment from surrounding cells
- cell shrinkage, blebbing of cell membrane = apoptotic bodies
- phagocytosis by macrophage of apoptotic bodies
21
Q
Excess apoptosis diseases
A
- huntington’s
- alzheimer’s
- parkinson’s
- traumatic brain injury
- stroke
22
Q
Inadequate apoptosis diseases
A
- cancer
- multiple sclerosis
- diabetes
- arthritis
- systemic lupu erythematosus
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
24
Q
Initator caspase
A
effector
-caspase 9 = stress
caspase 8 = death receptor
25
Effector caspase
executioner
- cleave specific cellular proteins = inactivation
- caspase 3, 6, 7
26
Adaptor proteins
bind to initiator caspases to activate
| Apaf-1 & FADD
27
Caspase activation regulated by _____ proteins
BCL-2 family proteins
28
Pro-apoptotic Bax/Bak
induce apoptosis by producing channels that release cytochrome c from mitochondrial outer membrane
29
Cytochrome C
binds to adapter protein (Apaf-1) which oligomerizes apoptosome
-activates initiator caspase-9
30
Activated caspase-9
cleaves effector caspase 3
31
Caspase 3
cleaves proteins leading to apoptotic body
32
BCL-2
proSURVIVAL BCL-2 inhibits apoptosis
| via preventing BAX/BAK oligomerization
33
BH3-only proteins
proAPOPTOTIC inhibit proSURVIVAL BCL-2 and may directly activate BAX/BAK
34
Oncogene
-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
Proto-oncogene:
the normal counterpart to an oncogene -- proper regulation
| -promote cell division and cell survival
36
Tumor suppressor genes
-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
Proto-oncogenes and tumor suppressor genes are ____ that regulate _____. Only when ___ do they ____
normal genes that regulate cell proliferation.
| mutate induce cancer or fail to prevent progression.
38
Examples of oncogenes
HER2
ras
c-myc
Bcr/Abl
39
Examples of tumor suppressor genes
Rb
| p53
40
Overexpression/hyperactivity of oncogenes induce signalling pathways that are ______________
- no longer growth factor dependent.
- oncogenes directly controls expression of cyclin D
- therefore GF independent
41
c-ras
inactive ras / GDP
active ras / GTP
-ras is an oncogene
42
Normal regulation of Ras protein
- 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
Mutant Ras protein is _______
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
Main contributors to cancer signalling pathways: (4)
- deregulation of growth factors
- hyperactive ras, myc, jun, fos, src (oncogenes)
- continuous grow/divide signal (constitutive)
- G1/S checkpoint compromised
45
Rb and p53 flow chart typically.
```
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
Rb acts as a brake on ____ progression
G1/S phase progression.
47
E2F
transcription factor that is inactivated by binding Rb.
| Otherwise, it transcribes genes needed for S phase.
48
What phosphorylates Rb? What does this do?
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
For S phase to progress what does the Rb and E2F look like.
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
Tumor suppressor genes: ______- of mutant cell cycle inhibitor p53/Rb allows for cell proliferation
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
Mutation in which 4 molecules can lead to cancer. (regarding tumor suppressor genes)
CycD
CycE
Rb
E2F
52
p53 gene
mutation in __ of cancers
leads to___
- mutation occurs in 50% of cancers
| - leads to genome instability
53
loss of p53 = genome instability
- cells escape apoptosis and divide with damaged DNA
| - these cells can accumulate MORE mutations which increase probability of tumor formation (two hit)
54
what is p53?
- 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
Name the processes that mutations in these genes affect in order: ras, Rb, p53/p21, p53/BAX
- signal transduction pathway
- checkpoint regulation (G1/S)
- response to checkpoint to DNA damage
- response or execution of apoptosis
56
3 ways to turn proto-oncogene into oncogene?
- 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
Gene amplification of proto-oncogene to oncogene. 2 specific genes.
c-myc or HER2
| Abnormal expression at abnormally elevated levels.
58
C-myc
transcription factor that regulates G1/S transition
59
HER2
receptor that activates MAPK signalling (proliferation)
60
Chromosome rearrangement (proto-oncogene to oncogene). 2 specific chromosomes and disease associated with
```
Philadelphia chromosome.
Fusion protein is hyperactive.
Chronic myelogenous leukemia.
Burkitt's lymphoma
Nearby regulatory sequence causes overproduction of c-myc protein.
```
61
fusion protein bcr-abl
tyrosine kinase activity is now constituitively active
62
Philadelphia chromosome
- chromosome 9 and 22
- reciprocal translocation produce philadelphia
- fusion protein of bcr (from small chr22) and abl (from large chr9)
63
Burkitt's lymphoma
- 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
Knudson's two hit hypothesis
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
Li-Fraumeni syndrome is caused by?
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
Cancers develop through accumulation of _______ in ____ and _____
accumulation of somatic mutations in proto-oncogenes and tumor supressor genes
67
Six essential alterations for tumorigenesis
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
Self-sufficiency in growth signals
- synthesize own growth factors
- growth factor receptor over expressed
- alteration in signal transduction
- over expression of transcription factors
- express mutant transcription factors
69
Insensitivity to antigrowth signals
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
Limitless replicative potential
- immortalize
- loss of p53
- inhibit Rb
- telomerase expression is overexpressed in cancer via end to end fusion
71
Sustained angiogenesis
- encourage blood vessel growth to provide O2 and nutrients
| - secrete endothelial growth factors
72
Tissue invasion and metastasis
-protease secretion
-altered expression of matrix binding proteins
-escape immune killing cells
tissue invasion, intravasation, survival in blood, extravasation, colonization
73
Evasion of apoptosis
-inactivate pro-apoptotic genes (FasR)
| activate anti-apoptotic protein genes (Bcl-2)
