TBL 4 Carcinogenesis Flashcards
(127 cards)
1
Q
____ is regulated cell death that is not associated with inflammatory response, whereas ____ is unregulated cell death that is associated with inflammation.
A
Apoptosis is regulated cell death that is not associated with inflammatory response, whereas Necrosis is unregulated cell death that is associated with inflammation.
2
Q
What are the two phases in apoptosis?
A
Latent phase: Death pathways are activated, but cell remains the same.
Execution phase: Apoptotic morphological structures begin to occur.
3
Q
_____ is the enzyme used to tag DNA with an extra fluorescently-tagged base at the __ ends.
It is used to detect apoptotic cell death.
A
TUNEL is the enzyme used to tag DNA with an extra fluorescently-tagged base at the 3’ ends.
4
Q
______ are enzymes which execute the apoptotic mechanisms directly.
A
Caspases
5
Q
What is the amino acid on the catalytic site of Caspases?
A
Cysteine
6
Q
_____ caspases trigger the cell death programmes and contain additional domains at their N-terminals.
A
Initiator
7
Q
Caspase 2 and 9 contain _____ whereas Caspase 8 and 10 contain _____ domains.
A
2 and 9 – CARD
8 and 10 – DED
8
Q
What cleaves and activates the effector caspases?
A
Initiator caspases
9
Q
Effector caspases can activate enzymes known as _______ which breaks down DNA into regular fragments for apoptosis.
A
Caspase-activated DNase (CAD)
10
Q
Fas is a death receptor found on many cells. It is (upregulated/downregulated) on infected cells. It is activated by its ligand, ____.
A
upregulated, FasL
11
Q
FADD is an adaptor protein that recruits _____ to form the death-inducing signalling complex (DISC).
A
Proscaspase 8
12
Q
The FLIP protein inhibites the death receptor activation of ______, by competitively binding to FADD on the trimerised receptor.
A
Caspase 8
13
Q
Death by default refers to programmed cell death initiated by endogenous signals that are dependent on (organelle).
A
Mitochondria
14
Q
The apoptosome is a large complex which contains Apaf-1, ATP, cyt-c and initiator procaspase __.
A
9
15
Q
In the apoptosome, the Apaf-1 contains CARD which binds to _____; ATPase domain which binds to ____; WD-40 repeats which bind to ____.
A
Caspase 9; ATP; cyt-c
16
Q
The binding of cytochrome-c to the ____ repeats on the Apaf-1 cause it to assemble into a wheel-like heptamer.
A
WD40
17
Q
Seven procaspase 9 molecules are brought together to the centre of the wheel, binding to CARD domains on the Apaf-1, and this allows for _____ to occur.
A
transcleavage
18
Q
Caspase 8, which is involved in the (extrinsic/intrinsic) pathway and Caspase 9, which is involved in the (extrinsic/intrinsic) pathway both activate Caspase _.
A
extrinsic; intrinsic; 3
19
Q
Caspase 8 also cleaves ____ protein, which enhances the release of mitochondrial proteins.
(costimulation between both pathways)
A
Bid
20
Q
The Bcl-2 family of proteins help to modulate the (organelle) intrinsic pathway of apoptosis.
A
mitochondrial
21
Q
The domain that all Bcl-2 proteins have in common is ___, and they therefore use this as a protein-protein interaction domain between different members of the family.
A
BH3
22
Q
(Anti/pro-apoptotic) Bcl-2 proteins include the Bcl-2, Bcl-xL.
(Anti/pro-apoptotic) Bcl-2 proteins include the Bid, Bax, Bad.
A
Anti; Pro
23
Q
The PI3’-kinase pathway promotes cell survival and proliferation. It is therefore (anti/pro-apoptotic.)
A
Anti
24
Q
Phosphatidylinositol 3’-kinase is a ___ kinase. It converts PIP2 to ___.
A
lipid; PIP3
25
PIP3 is recognised by the PH domain of the protein kinase ___/___, which is (anti/pro-apoptotic).
PFB/Akt, anti
26
PKB protein kinase phosphorylates Bad, which is then (activated/inactivated).
Bad is a (anti/pro-apoptotic) protein, hence inactivated Bad causes the cyt-c to (leave/remain) in the mitochondrial membrane.
Inactivated; pro; remain
27
PTEN is a ____ phosphatase, which dephosphorylates PIP3 back to ___, to counteract the effects of PI3-K signalling pathway.
lipid; PIP2
28
___ gene is a tumor suppressor gene, but unlike normal TS genes, it requires only ONE copy of the mutated gene to cause an effect. i.e. it acts in a dominant manner. This term is called haploinsufficiency.
p53
29
Inherited breast cancer is caused by inherited mutation in the ____ genes.
BRCA1/BRCA2
30
Chromosomal __________ occurs between chromosomes 9 and 22 in Chronic Myeloid Leukemia (CML).
This leads to a new fusion gene BCR-ABL1 on chromosome ___. This gene codes for a continually active ___________ (protein), leading to constant activation of downstream signalling cascades and overproduction of _______ (cells).
Chromosomal TRANSLOCATION occurs between chromosomes 9 and 22 in Chronic Myeloid Leukemia (CML).
This leads to a new fusion gene BCR-ABL1 on chromosome 22. This gene codes for a continually active TYROSINE KINASE RECEPTOR (protein), leading to constant activation of downstream signalling cascades and overproduction of GRANULOCYTES (cells).
31
Imatinib (Glivec) is a ___________ inhibitor, which is therefore used in the treatment of CML to prevent the overproduction of granulocytes.
Tyrosine Kinase
32
There are three methods to monitor disease progression of Leukemia:
1) Cytogenics; 2) FISH; 3) RT-PCR.
Amongst the three, _______ is the most accurate and sensitive, and is therefore used when the number of gene transcripts is greatly reduced.
RT-PCR
33
Chromosomal __________ occurs between chromosomes 15 and 17 in Acute Promyelocytic Leukemia (APML).
This leads to a new fusion gene PML-RARA. This gene codes for a protein which binds too (strongly/loosely) to DNA via enhanced interaction with co-repressors, (blocking/activating) transcription.
translocation; strongly; blocking
34
____ responds to all trans-retinoic acid (ATRA) therapy, which dissociates co-repressors, allowing for normal transcription and cell differentiation.
APML
35
Patients with K-ras mutation will lower the likelihood of response to _____ (drug) for colorectal cancer.
Cetuximab
36
Patients with EGFR mutation has a (greater/lower) likelihood of response to Geftinib for _______ (cancer).
greater; non-small cell lung cancer
37
Patients with _____ (gene) mutation is unlikely to respond to Dasatinib in CML.
BCR-ABL1
38
______ is the most vulnerable period of the cell cycle as cells are more easily killed, DNA damage cannot be repaired and gene transcription is silenced. (reduced metabolism)
Mitosis
39
___ phase occurs when the cell leaves the cell cycle and stops dividing.
G0
40
___ phase (10h) occurs after mitosis, and serves as a decision point whether the cell is to continue in the cell cycle.
G1
41
_ phase involves ______ ensuring that in the following mitotic division, the daughter cells possess the same amount of DNA as the parent cell originally had.
S; DNA Replication
42
In S phase, besides DNA replication, _____ synthesis is also increased. There is also replication of ______. In the case of mitochondria, the process needs to be coordinated with the replication of ____.
protein; organelles; mtDNA
43
___ phase (4h) occurs after DNA replication, and serves as a decision point.
G2
44
The centrosome consists of two ______ at right angles to each other. Each of them are made up of _______ microtubules.
centrioles; 9 triplets
45
The mother centriole and the daughter centriole are held together by ____________.
Interconnecting fibres
46
In the G1 phase, the mother and daughter centrioles ______, and ________ in the S phase, generating complete and new sets of centrioles by the time of mitosis.
separate; duplicate
47
The centrioles form a cloud of protein structures providing ________ sites for microtubules.
nucleation
48
In prophase, the ______ condenses to prevent DNA entanglement during segregation.
The duplicated ______ migrate to opposite poles of the nucleus and organise the assembly of ________.
chromatin; centrosomes; spindle microtubules
49
The DNA double helix first wraps around _____-charged _____ octamers with the presence of linker DNA.
positively; histone
50
The 10nm chromatin fibre further condenses around ___ histones and ______ DNA to form 30nm chromatin fiber.
H1; Linker
51
The 30nm chromatin fibre associates with ____ proteins and non-histone proteins to form ______ domains, which coil and condense further to form metaphase chromosomes.
scaffold; looped
52
____ are radial microtubule arrays which form around each centrosome, followed by meeting of radial arrays in prophase.
ASTERS
53
At _______ (stage), the nuclear membrane breaks down and the chromosomes attach to the mitotic spindle via _______ protein at the centromere region.
(Early) Prometaphase; kinetochore
54
At (early/late) Prometaphase, microtubule from opposite poles are captured by sister kinetochores. Chromosomes migrate to the equator of the cell.
Late
55
_______ senses when the kinetochore is bound to the microtubules.
CENP-E
56
At _______(stage), chromosomes are aligned singly at the equator of the spindle along the metaphase plate.
Metaphase
57
______ holds the sister chromatids together before segregation.
Cohesin
58
At Anaphase A, _____ is broken down, as kinetochore microtubules shorten, pulling the daughter chromosomes towards the opposite spindle poles.
Cohesin
59
At Anaphase B, daughter chromosomes migrate towards opposite poles, and the ________ migrate apart as the cell (elongates/shortens) due to the sliding of polar microtubules.
centrosomes; elongates
60
At ______ (stage), contractile ring of _____ and _____ filaments is assembled at the equator of the cell.
Telophase; actin and myosin
61
The M phase checkpoint occurs at _____ (stage), and checks for completion of chromosome alignment and spindle assembly.
Metaphase
62
The M phase checkpoint requires _____ and ____ protein kinases, which dissociate from kinetochore when chromosomes are properly attached to the spindle.
CENP-E and BUB
63
When all ____ kinases dissociate from the kinetochore, the cell is driven through the M checkpoint and anaphase proceeds.
BUB
64
Amphelic (normal) attachment of kinetochore to microtubules occurs when the kinetochore is attached to ___ microtubule from each centrosome.
one
65
Merotelic attachment occurs when one/both kinetochores are attached to _____ centrosomes.
both
66
Syntelic attachment occurs when BOTH kinetochores are attached to the ____ centrosome.
same
67
Monotelic attachment occurs when only ____ kinetochore is attached to a centrosome.
one
68
Taxanes and vinca alkaloids is a type of anti-cancer therapy that alter microtubule dynamics and produces unattached _______, causing long-term mitotic arrest.
kinetochores
69
Exit from G0 phase to enter mitosis and cell division is highly regulated, requiring ________ and ________ signalling cascades.
growth factors; intracellular
70
Some growth factors include _____ growth factor (EGF) and ______ growth factor (PDGF), which bind to and activate receptors.
epidermal; platelet-derived
71
Tyrosine phosphorylation on the RTK provide docking sites for ______ proteins which leads to protein-protein interactions.
adaptor
72
The transcription factor _____ plays a key role in the entry of quiescent cells into the cell cycle by stimulating the expression of cell cycle genes, and it peaks when _____ are present.
c-Myc; growth factors
73
Mitogenic growth factors bind to the transmembrane receptor _____. this leads to receptor activation by cross-________, activating ____ proteins.
RTK (Tyrosine Kinases); phosphorylation; adaptor
74
Anti-HER2 antibody (Herceptin) is a drug which targets the early stage of cellular signalling, by blocking the _______. (implicated in many breast cancers)
HER2 Receptor Tyrosine Kinase
75
Mitogenic growth factor pathway to stimulate mitosis:
_____ (ligand) binds to ______ (receptor), causing receptor to be cross-phosphorylated and activated. Adaptor protein ____ then binds to receptor and gets activated, associating itself with ____ (exchange factor), which can activate ____ (G protein).
Growth factors bind to RTK, causing receptor to be cross-phosphorylated and activated. Adaptor protein Grb2 then binds to receptor and gets activated, associating itself with SoS, which can activate Ras protein.
76
Ras protein must be bound to the ________ (organelle) to be activated. Many anti-cancer therapies are targeted at preventing Ras binding to _____.
plasma membrane
77
Ras is a _ protein. It is activated when bound to ____ and inactivated when bound to ____. It contains an internal _____ (enzyme) to hydrolyse the molecules.
GTP; GDP; GTPase
78
Internal GTPase of Ras might be a very slow process, hence the cell makes use of _____ proteins to promote the hydrolysis.
GTPase activating proteins (GAPs)
79
Ras mutations:
| Mutation of glycine to _____ can result in steric hinderance preventing ____ binding.
valine; GAP
80
Ras mutations:
| Mutation of ______ to leucine, which inhibits the GTPase activity and thus GTP hydrolysis.
glutamine-61
81
For growth-factor activated Ras transduction, the ____ cascade is used.
ERK (Extracellular signal-regulated kinase) cascade
82
Kinases specific to the ERK cascade (hence activated by Ras protein):
Kinase 1 - _____
Kinase 2 - _____
Kinase 3 - _____
Kinase 1 - Raf
Kinase 2 - MEK
Kinase 3 - ERK
83
The activated ___ protein may result in changes in gene expression of the ___ gene, resulting in cell proliferation.
ERK; Myc
84
The cyclin-Cdk complex (known as MPF) involved in the M phase is:
Mitotic cyclins A and B and Cdk1
85
To form active MPF,
1. Cyclin A and B must activate Cdk_ to form (inactive/active) MPF.
2. Requires activating phosphorylation by ___________.
3. Removal of inactivating phosphorylation ____ by phosphatase Cdc25.
To form active MPF,
1. Cyclin A and B must activate Cdk1 to form INACTIVE MPF.
2. Requires activating phosphorylation by Cdk-activating kinase (CAK)
3. Removal of inactivating phosphorylation (Wee1) by phosphatase Cdc25.
86
Phosphatase Cdc25 (which removes inactivating phosphorylation for MPF) is itself activated by phosphorylation by ____. (This is known as positive feedback.)
MPF
87
Cyclins activate Cdks and also alter _____.
substrate specificity
88
Cyclin D activates Cdk _ and _ to stimulate the synthesis of cyclin _.
Cyclin D activates Cdk 4 and 6 to stimulate the synthesis of cyclin E.
89
Rb gene is a _________ gene, and pRb is active in the (phosphorylated/unphosphorylated) state during G0, binding the inactive transcription factor ___, so that the target geen cannot be upregulated. (brake in the cell cycle)
tumor suppressor; unphosphorylated; E2F transcription factor
90
In proliferating cells, Cdk4/6-cyclinD / Cdk2-cyclinE (Start kinases) phosphorylates pRb and (activate/inactivate) it, (releasing/binding) E2F, allowing for the upregulation of target genes.
inactivate; releasing
91
______ act on active Cdk-cyclin complexes to inactivate them.
There are two families of inhibitors: ____ and ____.
CDK Inhibitors (CKI)
INK and KIP
92
INK family of CKIs are expressed during the __ phase of the cell cycle, act by competing for cyclin binding sites on Cdk____. This essentially displaces Cyclin D from the complex.
G1; Cdk4/6
93
CIP/KIP family of CKIs are expressed during the __ phase, and act by binding to the Cdk-cyclin complexes to inactivate the complex.
S
94
Cell-ECM adhesion will (increase/decrease) the chance of the cell entering S phase.
increase
(This is because cells require binding to the ECM to be fully competent to responding to soluble growth factors. This is known as ANCHORAGE DEPENDENCE.)
95
_____ (receptors) are heterodimer complexes of a and B subunits. They are the most important ECM receptors.
Integrins
96
Integrins recognise short specific peptide sequences.
E.g.: Fibronectin (glycoprotein) receptor binds the ____ motif.
RGD (arg-gly-asp)
97
Most integrins are linked via ____-binding proteins to the ____ cytoskeleton.
actin
Exception: a6B4 integrin complex is found in epithelial hemidesmosomes linked to the intermediate filament network instead.
98
Integrins cluster to form ________ involved in signal transduction.
focal adhesions
99
(Outside-in/Inside-out) signalling involves signal transduction using ECM receptors. Cells may receive information about its surroundings via its adhesion to the ECM.
Outside-in
100
(Outside-in/Inside-out) signalling involves signal generated inside the cell as the result of receptor-ligand binding can act on integrin complexes to alter their affinity for ECM binding.
Inside-out
101
The _____ (type/part) of the ECM is the most ideal for cellular differentiation.
Basal lamina/basement membrane
102
Both sets of signals - ________ dependence and _______ dependence must be present before the cell undergoes division.
There is cross-talk between the ECM and the growth factor signalling.
density (GFs) and anchorage (ECM) dependence
103
Long-term cell-cell contacts involve forming _______ between cells. These are specific to some cell types such as ______.
cell junctions; epithelial and endothelial cells
104
Cell-cell junctions are usually arrange either as _________ (zonula) or ________ (macula).
zonula - continuous belts
| macula - discrete spots
105
The presence of cell-cell junctions (inhibits/activates) cell proliferation and division.
inhibits
106
Cell-cell junctions are affected by ___ (ion) concentration.
At high ___ (ion) concentration, cell-cell junctions are stable and there is (high/low) cell proliferation.
Ca2+; low
Cell-cell junctions are also affected by the presence of adhesion-blocking antibodies.
107
_____ junctions are cell-cell junctions which have cytoplasmic links to the actin cytoskeleton.
There are a few components:
E-cadherin; B-catenin and a-catenin.
Adherens
108
______ is an important junction-associated molecule which is regulated primarily by the Wnt signalling pathway.
B-catenin
109
The APC gene product (tumor suppressor) is a protein involved in the degradation of the ______.
B-catenin
110
Loss of APC function results in the accumulation of ______, which translocates into the nucleus and activates the ______ transcription factor complex, upregulating a large number of cell cycle control genes.
B-catenin; Tcf/Lef-1
111
Most human cancers are _______ (epithelial origins).
carcinomas
112
__ checkpoint checks for the presence of growth factors, DNA damage, cell size, sufficient nutrients.
G1
113
__ checkpoint checks if DNA is successfully replicated without damage.
G2
114
__ checkpoint that occurs at ____ checks if there is successful formation of spindle fibres and attachment of spindle fibres to the chromosome kinetochores. (BUB proteins)
M; metaphase
115
_______ genes code for essential proteins involved in the maintenance of cell growth, division and differentiation.
Proto-oncogenes
116
__________ mutation convert proto-oncogenes to oncogenes.
Gain-of-function
117
Oncogenes act in a _______ manner.
dominant
118
Philadelphia chromosome involves a chromosomal translocation between chromosomes __ and __.
This produces a fusion protein ______, which causes RTK to be continually turned on.
Commonly found in ____ (Cancer).
9 (ABL) and 22 (BCR); BCR-ABL1; CML
119
________ genes typically encode proteins regulating cellular proliferation and maintaining cell integrity.
Tumor suppressor
120
Tumor suppressor genes usually act in a ________ manner.
| Exception: ____ protein
recessive; p53
121
_______ mutations occur in tumor suppressor genes, causing it to lose its original function
loss-of-function
122
Retinoblastoma is the malignant cancer of developing retinal cells due to mutation of both copies of ____________.
RB1 tumor suppressor gene
| encodes a nuclear protein that is involved in the regulation of the cell cycle
123
p53 protein is usually kept in check by ____, which inhibits the activity of p53 via negative feedback.
(p53 transcriptionally upregulates this protein.)
MDM2
124
The ___ gene is an important tumor suppressor gene implicated in colorectal carcinoma.
APC
125
APC participates in the ___ signalling pathway, helping to regulate the activity of ______, thereby preventing uncontrolled growth.
WNT; B-catenin
(recall: gene product of APC will degrade B-catenin in the cytoplasm, preventing it from forming Tcf/Lef-1 complex which will upregulate transcription of cell cycle genes.)
126
In colorectal cancer, at least three ________ genes and one ______ gene must be mutated for an epithelial cell to become metastatic.
3 tumor suppressor genes and 1 proto-oncogene
1. APC gene
2. K-ras gene
3. DCC gene
4. p53 gene
127
Mutations may be inherited for (tumor suppressor/onco) genes.
tumor suppressor
