Cancer bio Flashcards
(266 cards)
1
Q
What type of kinase is mTOR?
A
Serine/threonine
2
Q
mTOR is a downstream activation target of what pathway?
A
PI3K/AKT
3
Q
What mediates the activity of COX2?
A
PGE2
COX2 produces Prostaglandin H2 (PGH2), which is converted to PGE2 by cytosolic or membrane-associated PGE-2 synthases (PGES).
PGE2 exerts its activity by acting on a group of G-protein-coupled receptors, designated subtypes EP1, EP2, EP3 and EP4.
4
Q
At which point in the cell cycle is the CDK4/6-CyclinD complex active?
A
Early G1 - CyclinD-CDK4/6
Late G1 - CyclinE-CDK2
Early S- CyclinA-CDK2
Late S - CyclinA-CDK1
G2/M - CyclinB-CDK1
5
Q
At which point in the cell cycle is the CDK2/CyclinE complex active?
A
Late G1
Early G1 - CyclinD-CDK4/6 Late G1 - CyclinE-CDK2 Early S- CyclinA-CDK2 Late S - CyclinA-CDK1 G2/M - CyclinB-CDK1
6
Q
At which point in the cell cycle is the CDK2/CyclinA complex active?
A
Early S
Early G1 - CyclinD-CDK4/6 Late G1 - CyclinE-CDK2 Early S- CyclinA-CDK2 Late S - CyclinA-CDK1 G2/M - CyclinB-CDK1
7
Q
At which point in the cell cycle is the CDK1/CyclinA complex active?
A
Late S
Early G1 - CyclinD-CDK4/6 Late G1 - CyclinE-CDK2 Early S- CyclinA-CDK2 Late S - CyclinA-CDK1 G2/M - CyclinB-CDK1
8
Q
At which point in the cell cycle is the CDK1/CyclinB complex active?
A
G2/M
Early G1 - CyclinD-CDK4/6 Late G1 - CyclinE-CDK2 Early S- CyclinA-CDK2 Late S - CyclinA-CDK1 G2/M - CyclinB-CDK1
9
Q
p15, p16, p18, and p19 inhibit which cyclin/CDK complexes?
A
CyclinD/CDK4/6
…thus inhibiting G1/S transition
10
Q
p21, p27, and p57 inhibit which cyclin/CDK complexes?
A
CyclinE-CDK2 (late G1)
CyclinA-CDK2 (early S)
CyclinA-CDK1 (late S)
CyclinB-CDK1 (G2/M)
11
Q
A cell is overexpressing cyclin D1, allowing continuous proliferation. How do you reverse this?
A
Dominant negative CDK2
12
Q
Which enzyme produces siRNA?
A
DICER - rNAse that cleaves dsRNA into siRNA and miRNA
13
Q
miRNA and siRNA both activate what cellular complex?
A
RISC - RNA-induced silencing complex
14
Q
Where to miRNAs come from?
A
Introns/splice products –> DICER
15
Q
Hereditary nonpolyposis colorectal cancer is associated with defects in what cellular process?
A
MMR
16
Q
Xeroderma pigmentosum is associated with defects in what cellular process?
A
NER (Nucleotide excision repair)
17
Q
Li fraumeni syndrome is associated with a mutation in what gene?
A
p53 (autosomal dominant)
18
Q
Familial adenomatous polyposis is associated with a mutation in what gene?
A
APC (B-catenin pathway)
19
Q
Fanconi anemia is associated with a mutation in what genes?
A
Fanc/BRKA2
20
Q
Von Hippel Lindau mutation predisposes to what disease?
A
RCC
21
Q
PARP inhibitors are effective in patients who have deficient homologous recombination, caused by mutations or loss of which genes?
A
BRCA1
BRCA2
PALB2
Rad51 (due to loss of PTEN)
22
Q
Is MDM2 a proto-oncogene or tumor suppressor?
A
Proto-oncogene
MDM2 –> suppression of p53
23
Q
Is WT1 a proto-oncogene or tumor suppressor?
A
Tumor suppressor
Mutated in hereditary nephroblastoma
24
Q
Is Myc a proto-oncogene or tumor suppressor?
A
Proto-oncogene
c-MYC = constitutively active –> cell cycle progression, defects in apoptosis
25
What is the function of PTEN?
PTEN dephosphorylates PIP3-->PIP2, thus inhibiting the Ras/PI3K/AKT/mTOR pathway
26
Is VHLi a proto-oncogene or tumor suppressor?
tumor suppressor
VHL is a ubiquitin ligase that targets Hif-1a for destruction
mutations are recessive, but LOH is common
27
What targets Hif-1a for destruction
VHL, a ubiquitin ligase
28
Which of the following carcinogenic events is reversible?
promotion
initiation
progression
Promotion = proliferation not due to genomic mutation
```
Initiation = genomic mutations (irreversible)
Progression = accumulation of add'l mutations
```
29
True/False: Neoplasia is unlikely to develop if promotion occurs without initiation.
TRUE
30
Which of the following is a promoting agent?
- Croton oil
- Benzopyrine
- Sesame oil
- Radon
Croton oil
31
FeLV type C occurs in __?__% of cats. Which cell line is affected?
FeLV type C - <1% of cats
| early erythroid precursors effective
32
What are the relative levels of ALDH and ABCB1 in stem cells (high or low)
High ALDH
| High ABCB1
33
What are the characteristics of AnnexinV and propidium iodide uptake in early and late apoptosis?
Early apoptosis = AnnexinV+/PI -
| Late apoptosis = AnnexinV+/PI+
34
In which phase of the cell cycle is propidium iodide incorporation highest?
G2/M
```
PI = measure of DNA content
G1 = 2N G2 = 4N because DNA content is doubled during S phase
```
35
Which peak of a propidium idodie graph would be affected by taxanes?
4N/G2
PI = measure of DNA content
Peaks: G1 = 2N; G2 = 4N because DNA content is doubled during S phase
Taxane would trap cell in M phase/4N peak
36
What does SMAD do?
SMAD4 = effector transcription factor for TGF-B (cell cycle inhibition)
37
Which caspases constitute the initiator caspases?
8, 9, 10
```
Extrinsic = caspase 8, 10
Intrinsic = caspase 9 (cytochrome c + Apaf-1 --> apoptosome, cleaves caspase 9)
```
38
Which caspases are effector caspases?
Caspase 3, 6, 7
39
What forms the apoptosome, and what does it do?
Cytochrome c + Apaf-1
Cleaves caspase 9 --> activates intrinsic cascade
40
Name four factors that activate the extrinsic apoptotic caspase
DR5 (Death receptor 5)
Fas
TNFR
Granzyme
41
Following treatment with a new agent, you observe that the cells in your cell culture appear small, have condensed chromatin and membrane blebs. Are these cells undergoing apoptosis or necrosis?
Apoptosis
42
Following treatment with a new agent, you observe that the cells in your cell culture appear swollen, have amorphous densities visible in their mitochondria, and condensation of chromatin. Are these cells undergoing apoptosis or necrosis?
Necrosis
43
What are beclin-1 and p62 markers of?
Autophagy
Beclin-1 and p62 are markers of autophagy
44
How does Bcl produce apoptosis?
Release of cytochrome C from mitochondria
45
What is the MOA of CDKs?
Inactivation of growth suppressor proteins (ie Rb), allowing cell cycle to progress
**only active when paired with cyclins
46
High monocyte counts and high serum CCL2 (a monocyte chemokine) have been associated with what impact on prognosis in a variety of cancers?
High monocyte count = WORSE prognosis
**may be due in part to monocytes' role in allowing establishment of metastases, differentiation into metastasis-associated macrophages (MAMs), etc.
47
What is the impact of Patched dysfunction?
Cell proliferation
Patched is a negative regulator of Hedgehog signaling pathway; without it, Gli is cleaved to an activating transcription factor
48
What are the effects of increased SHH signaling?
activation of EMT, proliferation, invasion, and metastasis
49
What is the ligand for Frizzled and LRP receptors?
Wnt
50
What impact does the binding of Wnt to Frizzled or LRP have on B-catenin?
Wnt binding DECREASES B-catenin breakdown by the APC protein complex.
B-catenin acts as a major transcription factor
51
What impact does GSK3B have on B-catenin?
GSK3B degrades B-catenin
52
What family do bone morphogenic proteins belong to?
TGF-B
53
What roll does TGF-B play in cancer progression (ie tumor suppressor or promoter)?
BOTH
Initially exhibit suppressive effects; after malignant progression occurs TGF-B aids in evasion of immunity, EMT, and cell proliferation
54
Upon development of resistance to a RAF inhibitor, which of the following is the best strategy?
1) switch to MEK inhibitor
2) switch to Ras inhibitor
MEK inhibitor -- this is DOWNSTREAM of RAF (Ras is upstream of RAF pathway)
55
Which VEGF isoform is the most potently angiogenic?
VEGF-A
56
Which VEGF isoforms play a role in lymphangiogenesis?
VEGF C and D
57
Is FGF proangiogenic or antiangiogenic?
FGFa/b = proangiogenic
58
Are TGF a/b proangiogenic or antiangiogenic?
Transforming Growth Factor = proangiongenic
59
Is TNF alpha proangiogenic or antiangiogenic?
TNF = proangiongenic
60
Is G-CSF proangiogenic or antiangiogenic?
G-CSF = proangiogenic
61
Is IL-8 proangiogenic or antiangiogenic?
IL-8 = proangiogenic
62
Are proliferin and leptin proangiogenic or antiangiogenic?
Proliferin and leptin = proangiogenic
63
What impact do extracellular matrix-derived proteins have on angiogenesis?
Anti-angiogenic (Thrombospondin, Endostatin, arrestin, troponin-1)
64
Are thrombospondin and troponin-1 proangiogenic or antiangiogenic?
Thrombospondin and troponin = anti-angiogenic
65
Is interferon alpha proangiogenic or antiangiogenic?
IFN a = antiangiogenic
66
Are the cytokines IL-1, IL-12, and IL-18 proangiogenic or antiangiogenic?
IL-1, IL-12, and IL-18 = antiangiogenic
67
Are PEDF, PDGFR, and Platelet factor 4 proangiogenic or antiangiogenic?
PEDF, Platelet factor 4 = antiangiogenic
| PDGFR = antiangiogenic
68
Is ATIII proangiogenic or antiangiogenic?
ATIII = antiangiogenic
69
Are PEX and PT fragement proangiogenic or antiangiogenic?
PEX and PT fragement = antiangiogenic
70
Are tissue inhibitors of metalloproteinases proangiogenic or antiangiogenic?
tissue inhibitors of metalloproteinases (TIMPS) = antiangiogenic
71
What impact does endostatin have on endothelial cells?
Endostatin --> endothelial cell apoptosis
Blocks bFGF and VEGF
72
What happens to concentrations of endostatin and VEGF as dogs age?
Endostatin and VEGF decrease as dogs age
73
What is the receptor for thrombospondin, and what does binding result in?
CD36 = receptor for thrombospondin
| Binding elicits release of Fas-L from endothelium
74
Name PET-CT markers for hypoxia
```
18F-FDG
18F-FMISO
18F-FAZA
64Cu-ATSM
nitroimidazoles
Carbonic anhydrase IX
```
75
How is FDG transported in to the cell, and why does it accumulate intracellularly?
Transported by GLUT1
| Irreversibly phosphorylated by hexokinase II
76
What tissues are dark on T1 MRI?
air, bone, and water are dark on T1
Fat is white
77
What tissues are dark on T2 MRI?
air, bone, and fat are dark on T2 (water white)
78
Gadolinium MRI contrast agent primarily increases signal on which sequence?
T1
79
What appearance (hypoechoic or hyperechoic) is typical of malignant lesions with contrast harmonic ultrasound?
Hypoechoic
80
Prolonged treatment of feline SCC in vitro leads to what phenotypic change?
EMT
81
What is the mechanism of hypercalcemia in multiple myeloma?
RANKL-induced osteoclast activation
82
In which canine disease has Myc-IgH translocation been cytogenetically identified?
Lymphoma
83
Which HDAC inhibitor potentiates doxorubicin chemosensitivity in dogs with OSA?
Valproic acid
84
In which type of radiation side effect (acute or chronic) is overall treatment time important?
Acute
85
Late responding tissues have a (high or low) alpha/beta ratio?
Low a/b ratio
86
What does the TUNEL assay detect?
DNA fragmentation via detection of dsDNA breaks
Indicates late stages of apoptosis
Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labelling - TdT labels blunt ends of dsDNA breaks
87
At what temperature are the enzymes used in PCR active?
162F - NOT active at room temperature
Taq polymerase is isolated from a thermophilic bacterial species and thus resistant to denaturation at high temperatures
88
What cellular feature does the beta component of RT survival curve represent?
Cell repair mechanisms/repairable DNA damage
89
What is the main mechanism of cellular damage following ionizing radiation?
Radiolysis of water --> free radicals
90
What percentage of DNA damage caused by photon irradiation results from direct damage to the DNA?
~30%
91
What is the most radiosensitive phase of the cell cycle?
G2/M
92
What is unique about neutrons and alpha particles?
neutrons and alpha particles = high LET
93
How does gemcitabine act as a radiosensitizer?
Inhibition of RNR and DNApol
Depletion of dATP pools
Redistribution/Elimination of radio-resistant S-phase cells
Lowering apoptotic threshold
94
Which of the following genes are considered metastasis suppressors?
MEK, MKK4, KISS, NME, BrMS1
MKK4, KISS, NME, BrMS1 = metastasis suppressors
MEK = metastasis stimulator
95
Name 4 transcription factors that induce EMT.
Snail, Slug, Twist, ZEB1
96
Name two biological molecules that inhibit MMPs?
TIMPs
| alpha2 macroglobulins
97
What drugs inhibit MMPs?
doxycycline
chelators
hydroxamate inhibitors
98
Name 3 ways to assess tumor metabolism?
PET-CT
Gene expression array
RT-PCR
99
What impact does TGF-B signaling have in regards to EMT?
TGF-B signaling is a potent inducer of EMT
100
ZEB1, Snail, Slug, and Twist result in downregulation of what 4 classes of cell surface proteins?
cadherins, occluding, claudin, and desmoplakin
101
Name 5 pathways that act as extrinsic activators of EMT.
```
Wnt
Hedgehog
Notch
NFkB
TGF-B
```
102
What impact do Wnt and Hedgehog signaling have on Snail expression?
Increased expression of Snail --> downregulation of E-cadherin --> EMT
103
Describe the role of TGF-B in early tumorogenesis and late stages of tumor progression.
TGF-B acts as a tumor suppressor in early tumorogenesis and a metastatic promoter in late stages of tumor progression
104
TGF-B induces Smad signaling. What does Smad signaling promote?
EMT/ repression of E-cadherin
Smad2 and Smad3 bind with co- smad (Smad4) and this complex binds transcription factors like ZEB to repress E-cadherin during EMT
105
What does the loss of E-cadherin expression imply?
EMT
106
What role does B-catenin play in cell anchoring?
binds E-cadherin and α-catenin to the actin cytoskeleton
107
Which repair pathway is primarily responsible for repairing platinum-induced DNA damage?
NER
108
How are platinums inactivated in cytosol?
binding to sulfhydryl group (ie glutathione or metallothionine)
109
What is the typical PCR reaction cycle (ie temperatures for each step)?
1) 94C --> DNA denaturation
2) 53C --> primer hybridization
3) 72C --> Taq-polymerase DNA synthesis
110
What is comparative genomic hybridization?
DNA from malignant and normal cells is labeled with 2 different fluorochromes and hybridized to normal chromosomes -- regions of gain or loss are seen as changes in relative intensity ratio
111
In microarray analysis, genes whose expression is higher in tumor samples than the reference sample are typically shown in what color?
Red = higher expression in tumor
Green = lower expression in tumor
112
What impact does hypermethylation of CpG islands in gene promoter regions have on gene expression?
transcriptional silencing
113
What is considered the gold standard for methylation analysis?
Sodium bisulfite conversion
Converts unmethylated cystine to uracil while methylated cystine remains unchanged
114
What does the isotype control represent in flow cytometry?
an antibody targeting a protein not on the surface of the target cells with the same isotype (both heavy and light chain) as the antibody of interest. Cells that showed binding to the isotype are excluded from analysis as they represented non-specific binding
115
What is class switching?
maintenance of variable binding region of BCR with different Ig class
116
Which of the following cytokines increase APC activity: GM-CSF, G-CSF
both
GM-CSF is most effective
117
Which portion of immunoglobulin (Ig) is responsible for cytotoxicity?
Constant region (Fc)
118
Which portion of immunoglobulin (Ig) is responsible for antigen recognition?
Fab (fragment antigen-binding)
119
Which T-cell subtype producese IL-2?
TH1
120
Which T-cell subtype producese IL-4?
TH2
121
What outcomes does IL-2 promote?
Proliferation of T cells, NK cells, and B-cells
122
What outcomes does IL-4 promote?
TH2 cell differentiation
Isotype switching to IgE (B-cells)
Inhibition of IFN-g
123
What does IL-12 do?
Promotes TH1 differentiation (key TH1 cytokine)
Activates NK cells and cytotoxic T-cells
Stimulates IFN-g and TNF-a production
Decreases angiogenesis
124
TGF-B and IL-6 promote differentiation of what T-cell subset?
Th17 - these cells promote tissue inflammation
125
What do CD8+ effector cells do?
CD8 = cytotoxic Tcells
Lyse target cells presenting Ag in MHC I
Produce IFN-g
126
What doe CD4+ effector cells do?
CD4 = T helper cells
Secrete cytokines
Help CD8+ Tc cells and B cells
Activate macrophages
127
What are the activities of IL-6?
Proinflammatory, antiapoptotic
Support B-cell proliferation and plasma cell differentiation
Upregulation of PD-1 on monocytes
128
What are the activities of IL-8?
Proinflammatory
Chemotactic/activation factor for neutrophils and T-cells
Induces MMP2 activity
129
What are the activities of IL-10?
Immunosuppressive - produced by activated DCs, machrophages, and T-cells
Induces Tregs
130
Which cytokine induces Treg function?
IL-10
131
Which cytokine stimulates hematopoietic stem cell proliferation and platelet production?
IL-11
132
What are the activities of IL-13?
Promotes Th2 differentiation
| Inhibits inflammatory cytokine production by macrophages
133
What are the activities of IL-15?
T-cell growth factor, supports survival of CD8+ memory T-cells
Promotes NK cell activation
134
What are the activities of IL-17?
Proinflammatory promotion
135
Which cytokines promote Th2 differentiation?
IL-4
IL-13
IL-19
136
Which cells produce IFN-g, IFN-a, and IFN-B?
```
IFN-g = only NK and Tcells
IFN-a/B = all cells
```
137
Which cells produce TGF-B?
immunosuppressive cytokine primarily produced by macrophages and Tregs
138
What are the two "enabling hallmarks" of cancer?
Genomic instability
| Tumor-associated inflammation
139
What are zinc fingers and leucine fingers?
Transcription factors
140
Which cytokines are produced by TH1 and TH2 cells, respectively?
Th1 - IFN-f, IL-2, TNF --> cellular immunity
Th2 - IL-4, IL-5, IL-13 --> humoral immunity
141
What are the key features of a Th17 response?
IL-17 --> neutrophil recruitment and inflammation
142
What is the normal ratio of CD4:CD8 T cells in circulation?
2:1 CD4:CD8
143
What causes acquired CD4 deficiency in cats?
FIV
144
What portion of the Ig molecule determines antibody isotype?
Fc portion
145
Which cytokines promote IgE production?
IL-4, IL-5, IL-13
146
What is the most abundant antibody isotype, and where is it found?
IgA - GI tract, lungs
147
What are the activities of IFN-a and IFN-B?
Tumor cell apoptosis, inhibition of angiogenesis
Enhanced CTL effector function
NK cell activation
Modulation of MHC expression
148
What are the activities of IFN-g?
Promotes Th1 differentiation of CD4+ T cells
Macrophage activation
Increased MHC expression
149
What are the activities of TNF-a?
Pro-inflammatory
Induces NO production by macrophages
Induces tumor apoptosis
150
What are the activities of TGF-B?
Immunosuppressive
| Inhibits macrophage activation and B-cell growth
151
What do initiation, promotion, and progression entail in the classical model of carcinogenesis?
Initiation = carcinogen produces DNA damage - if not repaired before next division leads to fixation of mutation within genome
Promotion = clonal expansion of initiated cells due to proliferative advantage conferred by initiation event or promoting agent
Progression = benign lesions acquire ability to invade adjacent tissue and establish distant metastasis
152
What are the 3 potential mutational events that may result from unrepaired DNA damage?
a) error-prone replication --> nucleotide substitution
b) frame-shift mutations - often occurs when adducts are added to bases
c) DNA strand breaks
153
How many DNA damaging events are estimated to occur in each cell daily?
10,000
154
Describe 3 known promoting agents.
TPA (tetradecanoyl phorbol) - proinflammatory, induces oxidative stress resulting in a microenvironment favoring proliferation of transformed cells
TCDD (tetrachorodibenzo-p-dioxin)- inhibits apoptosis
phenobarbital - alters DNA methylation
155
Are germline mutations more likely to be found in cellular oncogenes or tumor suppressor genes?
Tumor suppressor genes
Germline mutation in oncogenes tends to be fatal
156
What does the rate at which drug-resistant variants arise in a cell population indirectly approximate?
indirect measure of genomic instability
157
How do deacetylated histones associated with DNA?
tightly coiled --> silencing of gene expression
158
Which DNA repair pathway is responsible for repair of microsatellites and insertion-deletion loops?
MMR
159
DNA glycosylases are vital to which DNA repair pathway?
Base excision repair
160
Which repair pathway is responsible for repair of spontaneous oxidative damage to DNA?
Base excision repair
161
What is the function of PARP?
Poly(ADP)-ribose polymerase catalyzes an intermediate step preceding DNA synth during base excision repair or repair of ssDNA breaks
162
What are the 4 steps in nucleotide excision repair?
1) recognition of DNA damage
2) excision of 24-32 residue oligonucleotide (short strand of ssDNA)
3) DNApol fills the gap
4) nick ligation
163
Which DNA repair pathway is responsible for the repair of 6,4-photoproducts?
nucleotide excision repair (specifically global genome repair)
164
Patients with xeroderma pigmentosum and Cockayne syndrome have deficiencies in which DNA repair pathway?
nucleotide excision repair
165
How does NER differ from MMR and BER?
NER removes a short segment of ssDNA to repair large adducts
BER pathway can correct only damaged bases that are removed by specific glycosylases, MMR pathway only targets mismatched base pairs
166
By which NER pathway - global genome repair or transcription-coupled repair - are cyclobutane pyrimidine dimers (CPDs) most efficiently repaired?
transcription-coupled repair
167
In which phases of the cell cycle can homologous recombination repair of ds DNA breaks occur?
S-phase and G2 - requires presence of homologous template (ie sister chromatid)
168
In which DNA repair pathway do BRCA1 and BRCA2 participate?
homologous recombination
169
In which DNA repair pathway is ATM active?
NHEJ
170
Which dsDNA break repair pathway is most error-prone?
NHEJ - usually results in insertion or deletion of a few bp at the break site during modification of DNA to produce ligatable ends
171
What type of DNA lesion does the Fanconi anemia pathway repair?
Interstrand crosslinks
172
What steps occur following recognition of an interstrand crosslink by FANCM?
recruits FA-core complex, coordinates downstream function of nucleases (ie FAN1), DNApol, NER components, and BRCA-mediates HR to restart the replication fork
173
Which proteins are responsible for sensing DNA DSBs and participating in cell cycle delay?
ATM, ATR, and DNA-PKs
174
Is an ATM dimer active or inactive?
Inactive --> activated by autophosphorylation of monomers in the presence of DNA damage
175
Which cell cycle regulators activate CHK1 and CHK2 in response to DNA damage?
ATM and ATR phosphorylate CHK1 and CHK2, leading to p53- and p21-dependent cell cycle arrest or apoptosis
176
Is TERT considered an oncogene?
Trick question, but mostly no. While TERT enables replicative immortality, cells immortalized through TERT expression retain normal morphology, response to external stress, and karyotype.
177
How does global hypomethylation contribute to genomic instability?
methylation of transposable DNA elements is thought to block their activation and movement, maintaining chromosomal stability. loss of methylation --> loss of stability
178
What role do MYC family proteins play?
Global transcription factors - thought to regulate ~15% of human genes
179
What is unique about the activation of ERBB2 (HER2)?
Requires dimerization with other family members, cannot bind ligand itself
180
What pathway is most prominently activated by mutant EGFR receptors?
MAPK, PI3K
181
What does the PI3KCA gene encode?
p110 catalytic subunit of PI3K
182
What are the components of the PI3K pathway?
PI3K converts PIP2-->PIP3 --> activates AKT --> activates mTOR
183
Activation of the PI3K/AKT pathway results in silencing of which proteins?
GSK-3
MDM2
BAD
184
What are the components of the MAPK pathway?
RAS --> RAF (ie BRAF) --> MEK --> ERK
185
Is a cell with a BRAF mutation also likely to harbor a RAS mutation?
No -- mutations in RAS and RAF proteins are mutually exclusive
186
IDH1 and 2 were identified as oncogenes by genomic methods. What is the mechanism by which they contribute to tumorigenesis?
Unknown
187
What tumor suppressor gene is mutated in hamartoma syndromes?
PTEN
188
In which DNA repair pathway is RAD51 involved?
HR (ds break repair)
189
Are BRCA1/2 oncogenes or tumor suppressor genes?
tumor suppressor
190
Name 2 families of CDK-inhibiting proteins?
INK4
CIP/KIP
others: MYT1 and WEE1
191
How are CDKs regulated to block cell cycle progression?
Ubiquitinated and degraded
192
What role does APC/C play in cell cycle progression?
E3 ligase that targets certain proteins for degradation
Activity in G1 phase is high
Ubiquitinates cell-cycle blocking proteins in G1 phase as well as mitotic CDKs (as this is post-anaphase)
193
Characterize the activity of APC/C and CDK1/2 during G1 phase?
High APC/C activity
Low CDK1/2 activity
also high: CDK4/6
194
When does CyclinA/CDK2 activity rise, and what does it trigger?
G1/S
| triggers DNA replication
195
Which CDK-cyclin complex increases in activity in late G2? What does this initiate?
CyclinB-CDK1
| triggers mitosis
196
When are CyclinB, Polo-like kinase, and the aurora kinases activated, and what do they regulate?
initiated in G2/M or prophase
| orchestrate early events of mitosis - shaping mitotic spindle and aligning chromatid pairs
197
What molecular events drive the progression of late anaphase and telophase?
loss of phosphorylation of CyclinB, PLK1, and aurora kinases
| increased APC/C activity
198
```
Which one of the BCL proteins is pro-apoptotic?
BCL-2
BCL-XL
BCL-Xs
BCL-W
```
BCL-Xs
199
Are the following proteins anti-apoptotic or pro-apoptotic? BIK, BIM, BID, PUMA
pro-apoptotic
200
Which proteins combine to form the apoptosome?
Cyt-c + APAF-1 + CASP9 (initiator caspase)
201
Which caspases are initiator caspases?
Caspase 2, 8, and 9
202
What are the IAPs and how do they function?
IAPs = inhibitors of apoptosis
ex: survivan, XIAP, IAP1/2
bind to caspases and inhibit function
203
What superfamily do the death receptors FAS, TNFR1, and DR3-6 belong to?
TNF receptor superfamily
204
What enzyme can be used as a marker of senscence?
B-galactosidase
205
Which initiator caspase is activated by extrinsic death signals?
Casp8
206
What cellular process is Beclin-1 required for?
Autophagy
207
Which chromosomal abnormality would indicate telomere failure?
End-to-end fusions
208
Name 3 inhibitors of angiogenesis.
Thrombospondin-1
Angiostatin (fragments of plasmin)
Endostatin (fragments of type 18 collagen)
209
Following radiation-induced cell damage, is H2AX likely to be phosphorylated or unphosphorylated?
following DNA damage, ATM phosphorylates H2AX, which is then activated an localizes to sites of DNA ds breaks
210
What affect does MDM2 have on p53?
ubiquitin ligase that targets p53 for degradation
211
What affect do ATM and Chk2 have on p53?
Phosphorylate and stabilize p53
212
What affect does p53 have on p21?
p53 increases expression of p21, which prevents Rb phosphorylation and cell cycle progression
213
What does the shoulder region on a radiation survival curve represent?
non-lethal damage repair (ie B component)
214
What is the significance of N-cadherin expression?
Increased propensity for invasion/metastasis
N-cadherin is normally expressed in migrating neurons and mesenchymal cells during organogenesis, often replaces E-cadherin in invasive carcinoma cells
215
What are the 6 classic hallmarks of cancer?
```
Sustaining proliferative signaling
Evading growth suppressors
Enabling replicative immortality
Activating invasion and metastasis
Inducing angiogenesis
Resisting death
```
216
What ion acts as a cofactor for MMPs?
Zinc
217
What is uPAR?
urokinase type plasminogen activating receptor (serine protease)
218
What are TIMPs?
Tissue inhibitors of metalloproteinases
219
What are focal adhesion plaques?
anchor points between integrins and the ECM
220
Which binds larger molecules: MHC class I or class II?
Class II - larger binding cleft
The binding cleft is the site of greatest diversity
221
Which APCs are capable of activating naive T-cells?
Dendritic cells
222
What is CD28 and what are its ligands?
CD28= T-cell activating costimulatory receptor
ligands = CD80, CD86
results in IL-2 production
223
Is a viral infection more likely to induce a Th1 or Th2 response?
Th1 - drives a primarily CTL/CD8+ response
224
Is a bacterial infection more likely to induce a Th1 or Th2 response?
Th2 - drives humoral immunity
225
Which cytokines are produced by Th1 cells?
IL-2, IL-12
TNFa
IFNg
226
What is the primary cytokine produce by Th2 cells?
IL-4
227
What does CTLA-4 do?
accumulates CD80/CD86, activates IDO and inhibits T cell proliferation and signaling
228
Where are PDL1 and PDL2 expressed?
PDL1 - many tissues
| PDL2 - primarily APCs
229
What does PD-1 do?
blocks function and survival of effector T cells
230
Which cells can impart anergy on mature T-cells once they have left the thymus?
Dendritic cells
231
Are T-regs antigen specific?
Yes, but they suppress in a nonspecific manner -- ie they must encounter self antigen but go on to suppress other nearby T cells reacting to various antigens
232
What do tolerogenic DCs do?
Secrete TGF-B, thereby inducing Tregs
233
How does IDO inhibit T cell proliferation?
Depletion of tryptophan
234
How should monoclonal antibodies be engineered to best harness ADCC?
-select those Abs that bind well to activating FcRs and poorly to inhibitory receptors such as FcgIIB
235
Which small molecule inhibitor is a substrate for ABCG2/BCRP?
gefitinib
236
Hypermethylation and of the promoter region of p16 (CDKN2A) resulting in silencing is a common alteration in cancer. What is the function of p16/CDKN2A?
CDK inhibitor
| phosphorylates Rb
237
Tumor suppressor gene silencing is often achieved by both promoter methylation and histone deacetylation. Are HDACi's alone sufficient in reversing gene silencing?
No, both demethylation and HDACi must be achieved to reactivate genes
238
What is the MOA of bortezomib?
Proteasome inhibitor --> induces apoptosis thru death effector caspase activation, upregulates p53, p21, Rb
239
What is the HUMARA assay?
Human androgen receptor assay - takes advantage of polymorphic short tandem repeat of CAG within the human AR gene to demonstrate clonal inactivation of X chromosome (ie Barr body inactivation)
240
Differentiate M1 and M2 macrophages in terms of cytokines produced and impact on tumors.
M1 --> IL-12, anti-tumor
| M2 --> IL-10, promote tumor progression
241
Is NFkB pro- or anti-inflammatory?
Pro-inflammatory, also contributes to tumor progression.
242
Is NFkB pro- or anti-inflammatory?
Pro-inflammatory, also contributes to tumor progression.
243
What is the function of p16?
CDK 4/6 inhibitor
244
What is the function of p21/Waf-1?
universal CDK inhibitor (exc CDK 2 and 4)
245
How is the canonical Wnt pathway activated, and what impact does this have on B-catenin?
binding of Wnt ligand to Frizzled
Inhibits B-catenin phosphorylation and breakdown
B-catenin translocates to nucleus and interacts with DNA binding proteins
246
Which of the Wnt pathways is B-catenin independent?
Non-cannonical Wnt
| May antagonize B catenin signaling
247
What family of transcription factors is activated by B-catenin signaling?
T-cell factor/lymphoid enhancer factor (Tcf/Lef)
248
When the null hypothesis is false and you fail to reject it, you make a type ? error. How can this be avoided?
Type II error = false +
| Solution = larger sample size
249
When the null hypothesis is true and you reject it, you make a type ? error. How can this be avoided?
Type I error = false -
| solution = lower alpha (limit of significance)
250
How does Annexin V detect apoptosis?
Binds phosphatidyl serine translocated to outer membrane
251
What is TERT, and what % of canine tumors express TERT?
telomerase reverse transcriptase
| >90%
252
What is phospho-H2AX a marker for?
DNA DSBs
253
What are cathepsins?
proteases
254
What is the minimum # of patients in a Phase II trial required to detect efficacy (25% response rate)?
9
255
What is Myc?
transcription factor that plays a role in cell cycle progression, apoptosis and cellular transformation
256
On which cells are PD-1 and CTLA-4 expressed?
PD-1: activated T cells, B cells, and macrophages
| CTLA-4: upregulated on activated T cells, constitutively expressed on T regs
257
What are the functions of PD-1?
Inhibits TCR signaling
Inhibits T cell proliferation
Inhibits induction of cytokines (IFNg, IL-2, TNFa)
258
Where are the 2 ligands for PD-1 expressed?
PDL-1 - inducible in many tissues
| PDL-2 - macrophages and dendritic cells
259
What type of kinases are RAF proteins?
serine/threonine
| activated by RAS
260
What do RAF proteins activate?
MEK --> MAPK
261
Where are matrix-binding areas located on normal epithelial cells?
basal aspect
| mesenchymal polarity is reversed, allowing migration
262
What are the 3 types of EMT?
Type I - embryogenesis/organ development
Type II - fibrosis
Type III - metastasis
263
What molecular events denote Mesenchymal to Epithelial transition once cells reach a site of colonization?
upregulation of E-cadherin and B-catenin
264
What causes telomeric attrition?
inability of DNA machinery to efficiently replicate 5' ends of linear chromosomes
265
How long are human, canine, and murine telomeres?
human - 10-15kbp
canine - 12-23kbp (similar)
mouse - 40-60kbp (4-6X as long as humans)
266
Which species are more likely to express somatic telomerase: human, dog, mouse, chicken
mouse and chicken
