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Onco Board Review > Cancer bio > Flashcards

Cancer bio Flashcards

1
Q

What type of kinase is mTOR?

A

Serine/threonine

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2
Q

mTOR is a downstream activation target of what pathway?

A

PI3K/AKT

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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.

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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

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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
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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
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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
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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
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9
Q

p15, p16, p18, and p19 inhibit which cyclin/CDK complexes?

A

CyclinD/CDK4/6

…thus inhibiting G1/S transition

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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)

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11
Q

A cell is overexpressing cyclin D1, allowing continuous proliferation. How do you reverse this?

A

Dominant negative CDK2

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12
Q

Which enzyme produces siRNA?

A

DICER - rNAse that cleaves dsRNA into siRNA and miRNA

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13
Q

miRNA and siRNA both activate what cellular complex?

A

RISC - RNA-induced silencing complex

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14
Q

Where to miRNAs come from?

A

Introns/splice products –> DICER

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15
Q

Hereditary nonpolyposis colorectal cancer is associated with defects in what cellular process?

A

MMR

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16
Q

Xeroderma pigmentosum is associated with defects in what cellular process?

A

NER (Nucleotide excision repair)

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17
Q

Li fraumeni syndrome is associated with a mutation in what gene?

A

p53 (autosomal dominant)

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18
Q

Familial adenomatous polyposis is associated with a mutation in what gene?

A

APC (B-catenin pathway)

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19
Q

Fanconi anemia is associated with a mutation in what genes?

A

Fanc/BRKA2

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20
Q

Von Hippel Lindau mutation predisposes to what disease?

A

RCC

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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)

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22
Q

Is MDM2 a proto-oncogene or tumor suppressor?

A

Proto-oncogene

MDM2 –> suppression of p53

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23
Q

Is WT1 a proto-oncogene or tumor suppressor?

A

Tumor suppressor

Mutated in hereditary nephroblastoma

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24
Q

Is Myc a proto-oncogene or tumor suppressor?

A

Proto-oncogene

c-MYC = constitutively active –> cell cycle progression, defects in apoptosis

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25
Q

What is the function of PTEN?

A

PTEN dephosphorylates PIP3–>PIP2, thus inhibiting the Ras/PI3K/AKT/mTOR pathway

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26
Q

Is VHLi a proto-oncogene or tumor suppressor?

A

tumor suppressor

VHL is a ubiquitin ligase that targets Hif-1a for destruction
mutations are recessive, but LOH is common

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27
Q

What targets Hif-1a for destruction

A

VHL, a ubiquitin ligase

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28
Q

Which of the following carcinogenic events is reversible?
promotion
initiation
progression

A

Promotion = proliferation not due to genomic mutation

Initiation = genomic mutations (irreversible)
Progression = accumulation of add'l mutations
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29
Q

True/False: Neoplasia is unlikely to develop if promotion occurs without initiation.

A

TRUE

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30
Q

Which of the following is a promoting agent?

  • Croton oil
  • Benzopyrine
  • Sesame oil
  • Radon
A

Croton oil

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31
Q

FeLV type C occurs in __?__% of cats. Which cell line is affected?

A

FeLV type C - <1% of cats

early erythroid precursors effective

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32
Q

What are the relative levels of ALDH and ABCB1 in stem cells (high or low)

A

High ALDH

High ABCB1

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33
Q

What are the characteristics of AnnexinV and propidium iodide uptake in early and late apoptosis?

A

Early apoptosis = AnnexinV+/PI -

Late apoptosis = AnnexinV+/PI+

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34
Q

In which phase of the cell cycle is propidium iodide incorporation highest?

A

G2/M

PI = measure of DNA content
G1 = 2N  G2 = 4N because DNA content is doubled during S phase
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35
Q

Which peak of a propidium idodie graph would be affected by taxanes?

A

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

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36
Q

What does SMAD do?

A

SMAD4 = effector transcription factor for TGF-B (cell cycle inhibition)

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37
Q

Which caspases constitute the initiator caspases?

A

8, 9, 10

Extrinsic = caspase 8, 10
Intrinsic = caspase 9 (cytochrome c + Apaf-1 --> apoptosome, cleaves caspase 9)
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38
Q

Which caspases are effector caspases?

A

Caspase 3, 6, 7

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39
Q

What forms the apoptosome, and what does it do?

A

Cytochrome c + Apaf-1

Cleaves caspase 9 –> activates intrinsic cascade

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40
Q

Name four factors that activate the extrinsic apoptotic caspase

A

DR5 (Death receptor 5)
Fas
TNFR
Granzyme

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41
Q

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?

A

Apoptosis

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42
Q

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?

A

Necrosis

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43
Q

What are beclin-1 and p62 markers of?

A

Autophagy

Beclin-1 and p62 are markers of autophagy

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44
Q

How does Bcl produce apoptosis?

A

Release of cytochrome C from mitochondria

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45
Q

What is the MOA of CDKs?

A

Inactivation of growth suppressor proteins (ie Rb), allowing cell cycle to progress

**only active when paired with cyclins

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46
Q

High monocyte counts and high serum CCL2 (a monocyte chemokine) have been associated with what impact on prognosis in a variety of cancers?

A

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.

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47
Q

What is the impact of Patched dysfunction?

A

Cell proliferation

Patched is a negative regulator of Hedgehog signaling pathway; without it, Gli is cleaved to an activating transcription factor

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48
Q

What are the effects of increased SHH signaling?

A

activation of EMT, proliferation, invasion, and metastasis

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49
Q

What is the ligand for Frizzled and LRP receptors?

A

Wnt

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50
Q

What impact does the binding of Wnt to Frizzled or LRP have on B-catenin?

A

Wnt binding DECREASES B-catenin breakdown by the APC protein complex.

B-catenin acts as a major transcription factor

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51
Q

What impact does GSK3B have on B-catenin?

A

GSK3B degrades B-catenin

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52
Q

What family do bone morphogenic proteins belong to?

A

TGF-B

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53
Q

What roll does TGF-B play in cancer progression (ie tumor suppressor or promoter)?

A

BOTH

Initially exhibit suppressive effects; after malignant progression occurs TGF-B aids in evasion of immunity, EMT, and cell proliferation

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54
Q

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

A

MEK inhibitor – this is DOWNSTREAM of RAF (Ras is upstream of RAF pathway)

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55
Q

Which VEGF isoform is the most potently angiogenic?

A

VEGF-A

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56
Q

Which VEGF isoforms play a role in lymphangiogenesis?

A

VEGF C and D

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57
Q

Is FGF proangiogenic or antiangiogenic?

A

FGFa/b = proangiogenic

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58
Q

Are TGF a/b proangiogenic or antiangiogenic?

A

Transforming Growth Factor = proangiongenic

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59
Q

Is TNF alpha proangiogenic or antiangiogenic?

A

TNF = proangiongenic

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60
Q

Is G-CSF proangiogenic or antiangiogenic?

A

G-CSF = proangiogenic

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61
Q

Is IL-8 proangiogenic or antiangiogenic?

A

IL-8 = proangiogenic

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62
Q

Are proliferin and leptin proangiogenic or antiangiogenic?

A

Proliferin and leptin = proangiogenic

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63
Q

What impact do extracellular matrix-derived proteins have on angiogenesis?

A

Anti-angiogenic (Thrombospondin, Endostatin, arrestin, troponin-1)

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64
Q

Are thrombospondin and troponin-1 proangiogenic or antiangiogenic?

A

Thrombospondin and troponin = anti-angiogenic

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65
Q

Is interferon alpha proangiogenic or antiangiogenic?

A

IFN a = antiangiogenic

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66
Q

Are the cytokines IL-1, IL-12, and IL-18 proangiogenic or antiangiogenic?

A

IL-1, IL-12, and IL-18 = antiangiogenic

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67
Q

Are PEDF, PDGFR, and Platelet factor 4 proangiogenic or antiangiogenic?

A

PEDF, Platelet factor 4 = antiangiogenic

PDGFR = antiangiogenic

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68
Q

Is ATIII proangiogenic or antiangiogenic?

A

ATIII = antiangiogenic

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69
Q

Are PEX and PT fragement proangiogenic or antiangiogenic?

A

PEX and PT fragement = antiangiogenic

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70
Q

Are tissue inhibitors of metalloproteinases proangiogenic or antiangiogenic?

A

tissue inhibitors of metalloproteinases (TIMPS) = antiangiogenic

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71
Q

What impact does endostatin have on endothelial cells?

A

Endostatin –> endothelial cell apoptosis

Blocks bFGF and VEGF

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72
Q

What happens to concentrations of endostatin and VEGF as dogs age?

A

Endostatin and VEGF decrease as dogs age

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73
Q

What is the receptor for thrombospondin, and what does binding result in?

A

CD36 = receptor for thrombospondin

Binding elicits release of Fas-L from endothelium

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74
Q

Name PET-CT markers for hypoxia

A 
18F-FDG
18F-FMISO
18F-FAZA
64Cu-ATSM
nitroimidazoles
Carbonic anhydrase IX
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75
Q

How is FDG transported in to the cell, and why does it accumulate intracellularly?

A

Transported by GLUT1

Irreversibly phosphorylated by hexokinase II

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76
Q

What tissues are dark on T1 MRI?

A

air, bone, and water are dark on T1

Fat is white

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77
Q

What tissues are dark on T2 MRI?

A

air, bone, and fat are dark on T2 (water white)

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78
Q

Gadolinium MRI contrast agent primarily increases signal on which sequence?

A

T1

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79
Q

What appearance (hypoechoic or hyperechoic) is typical of malignant lesions with contrast harmonic ultrasound?

A

Hypoechoic

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80
Q

Prolonged treatment of feline SCC in vitro leads to what phenotypic change?

A

EMT

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81
Q

What is the mechanism of hypercalcemia in multiple myeloma?

A

RANKL-induced osteoclast activation

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82
Q

In which canine disease has Myc-IgH translocation been cytogenetically identified?

A

Lymphoma

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83
Q

Which HDAC inhibitor potentiates doxorubicin chemosensitivity in dogs with OSA?

A

Valproic acid

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84
Q

In which type of radiation side effect (acute or chronic) is overall treatment time important?

A

Acute

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85
Q

Late responding tissues have a (high or low) alpha/beta ratio?

A

Low a/b ratio

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86
Q

What does the TUNEL assay detect?

A

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

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87
Q

At what temperature are the enzymes used in PCR active?

A

162F - NOT active at room temperature

Taq polymerase is isolated from a thermophilic bacterial species and thus resistant to denaturation at high temperatures

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88
Q

What cellular feature does the beta component of RT survival curve represent?

A

Cell repair mechanisms/repairable DNA damage

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89
Q

What is the main mechanism of cellular damage following ionizing radiation?

A

Radiolysis of water –> free radicals

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90
Q

What percentage of DNA damage caused by photon irradiation results from direct damage to the DNA?

A

~30%

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91
Q

What is the most radiosensitive phase of the cell cycle?

A

G2/M

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92
Q

What is unique about neutrons and alpha particles?

A

neutrons and alpha particles = high LET

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93
Q

How does gemcitabine act as a radiosensitizer?

A

Inhibition of RNR and DNApol
Depletion of dATP pools
Redistribution/Elimination of radio-resistant S-phase cells
Lowering apoptotic threshold

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94
Q

Which of the following genes are considered metastasis suppressors?
MEK, MKK4, KISS, NME, BrMS1

A

MKK4, KISS, NME, BrMS1 = metastasis suppressors

MEK = metastasis stimulator

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95
Q

Name 4 transcription factors that induce EMT.

A

Snail, Slug, Twist, ZEB1

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96
Q

Name two biological molecules that inhibit MMPs?

A

TIMPs

alpha2 macroglobulins

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97
Q

What drugs inhibit MMPs?

A

doxycycline
chelators
hydroxamate inhibitors

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98
Q

Name 3 ways to assess tumor metabolism?

A

PET-CT
Gene expression array
RT-PCR

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99
Q

What impact does TGF-B signaling have in regards to EMT?

A

TGF-B signaling is a potent inducer of EMT

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100
Q

ZEB1, Snail, Slug, and Twist result in downregulation of what 4 classes of cell surface proteins?

A

cadherins, occluding, claudin, and desmoplakin

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101
Q

Name 5 pathways that act as extrinsic activators of EMT.

A 
Wnt
Hedgehog
Notch
NFkB
TGF-B
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102
Q

What impact do Wnt and Hedgehog signaling have on Snail expression?

A

Increased expression of Snail –> downregulation of E-cadherin –> EMT

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103
Q

Describe the role of TGF-B in early tumorogenesis and late stages of tumor progression.

A

TGF-B acts as a tumor suppressor in early tumorogenesis and a metastatic promoter in late stages of tumor progression

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104
Q

TGF-B induces Smad signaling. What does Smad signaling promote?

A

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

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105
Q

What does the loss of E-cadherin expression imply?

A

EMT

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106
Q

What role does B-catenin play in cell anchoring?

A

binds E-cadherin and α-catenin to the actin cytoskeleton

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107
Q

Which repair pathway is primarily responsible for repairing platinum-induced DNA damage?

A

NER

108
Q

How are platinums inactivated in cytosol?

A

binding to sulfhydryl group (ie glutathione or metallothionine)

109
Q

What is the typical PCR reaction cycle (ie temperatures for each step)?

A

1) 94C –> DNA denaturation
2) 53C –> primer hybridization
3) 72C –> Taq-polymerase DNA synthesis

110
Q

What is comparative genomic hybridization?

A

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
Q

In microarray analysis, genes whose expression is higher in tumor samples than the reference sample are typically shown in what color?

A

Red = higher expression in tumor

Green = lower expression in tumor

112
Q

What impact does hypermethylation of CpG islands in gene promoter regions have on gene expression?

A

transcriptional silencing

113
Q

What is considered the gold standard for methylation analysis?

A

Sodium bisulfite conversion

Converts unmethylated cystine to uracil while methylated cystine remains unchanged

114
Q

What does the isotype control represent in flow cytometry?

A

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
Q

What is class switching?

A

maintenance of variable binding region of BCR with different Ig class

116
Q

Which of the following cytokines increase APC activity: GM-CSF, G-CSF

A

both

GM-CSF is most effective

117
Q

Which portion of immunoglobulin (Ig) is responsible for cytotoxicity?

A

Constant region (Fc)

118
Q

Which portion of immunoglobulin (Ig) is responsible for antigen recognition?

A

Fab (fragment antigen-binding)

119
Q

Which T-cell subtype producese IL-2?

A

TH1

120
Q

Which T-cell subtype producese IL-4?

A

TH2

121
Q

What outcomes does IL-2 promote?

A

Proliferation of T cells, NK cells, and B-cells

122
Q

What outcomes does IL-4 promote?

A

TH2 cell differentiation
Isotype switching to IgE (B-cells)
Inhibition of IFN-g

123
Q

What does IL-12 do?

A

Promotes TH1 differentiation (key TH1 cytokine)
Activates NK cells and cytotoxic T-cells
Stimulates IFN-g and TNF-a production
Decreases angiogenesis

124
Q

TGF-B and IL-6 promote differentiation of what T-cell subset?

A

Th17 - these cells promote tissue inflammation

125
Q

What do CD8+ effector cells do?

A

CD8 = cytotoxic Tcells

Lyse target cells presenting Ag in MHC I
Produce IFN-g

126
Q

What doe CD4+ effector cells do?

A

CD4 = T helper cells

Secrete cytokines
Help CD8+ Tc cells and B cells
Activate macrophages

127
Q

What are the activities of IL-6?

A

Proinflammatory, antiapoptotic
Support B-cell proliferation and plasma cell differentiation
Upregulation of PD-1 on monocytes

128
Q

What are the activities of IL-8?

A

Proinflammatory
Chemotactic/activation factor for neutrophils and T-cells
Induces MMP2 activity

129
Q

What are the activities of IL-10?

A

Immunosuppressive - produced by activated DCs, machrophages, and T-cells
Induces Tregs

130
Q

Which cytokine induces Treg function?

A

IL-10

131
Q

Which cytokine stimulates hematopoietic stem cell proliferation and platelet production?

A

IL-11

132
Q

What are the activities of IL-13?

A

Promotes Th2 differentiation

Inhibits inflammatory cytokine production by macrophages

133
Q

What are the activities of IL-15?

A

T-cell growth factor, supports survival of CD8+ memory T-cells
Promotes NK cell activation

134
Q

What are the activities of IL-17?

A

Proinflammatory promotion

135
Q

Which cytokines promote Th2 differentiation?

A

IL-4
IL-13
IL-19

136
Q

Which cells produce IFN-g, IFN-a, and IFN-B?

A 
IFN-g = only NK and Tcells
IFN-a/B = all cells
137
Q

Which cells produce TGF-B?

A

immunosuppressive cytokine primarily produced by macrophages and Tregs

138
Q

What are the two “enabling hallmarks” of cancer?

A

Genomic instability

Tumor-associated inflammation

139
Q

What are zinc fingers and leucine fingers?

A

Transcription factors

140
Q

Which cytokines are produced by TH1 and TH2 cells, respectively?

A

Th1 - IFN-f, IL-2, TNF –> cellular immunity

Th2 - IL-4, IL-5, IL-13 –> humoral immunity

141
Q

What are the key features of a Th17 response?

A

IL-17 –> neutrophil recruitment and inflammation

142
Q

What is the normal ratio of CD4:CD8 T cells in circulation?

A

2:1 CD4:CD8

143
Q

What causes acquired CD4 deficiency in cats?

A

FIV

144
Q

What portion of the Ig molecule determines antibody isotype?

A

Fc portion

145
Q

Which cytokines promote IgE production?

A

IL-4, IL-5, IL-13

146
Q

What is the most abundant antibody isotype, and where is it found?

A

IgA - GI tract, lungs

147
Q

What are the activities of IFN-a and IFN-B?

A

Tumor cell apoptosis, inhibition of angiogenesis
Enhanced CTL effector function
NK cell activation
Modulation of MHC expression

148
Q

What are the activities of IFN-g?

A

Promotes Th1 differentiation of CD4+ T cells
Macrophage activation
Increased MHC expression

149
Q

What are the activities of TNF-a?

A

Pro-inflammatory
Induces NO production by macrophages
Induces tumor apoptosis

150
Q

What are the activities of TGF-B?

A

Immunosuppressive

Inhibits macrophage activation and B-cell growth

151
Q

What do initiation, promotion, and progression entail in the classical model of carcinogenesis?

A

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
Q

What are the 3 potential mutational events that may result from unrepaired DNA damage?

A

a) error-prone replication –> nucleotide substitution
b) frame-shift mutations - often occurs when adducts are added to bases
c) DNA strand breaks

153
Q

How many DNA damaging events are estimated to occur in each cell daily?

A

10,000

154
Q

Describe 3 known promoting agents.

A

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
Q

Are germline mutations more likely to be found in cellular oncogenes or tumor suppressor genes?

A

Tumor suppressor genes

Germline mutation in oncogenes tends to be fatal

156
Q

What does the rate at which drug-resistant variants arise in a cell population indirectly approximate?

A

indirect measure of genomic instability

157
Q

How do deacetylated histones associated with DNA?

A

tightly coiled –> silencing of gene expression

158
Q

Which DNA repair pathway is responsible for repair of microsatellites and insertion-deletion loops?

A

MMR

159
Q

DNA glycosylases are vital to which DNA repair pathway?

A

Base excision repair

160
Q

Which repair pathway is responsible for repair of spontaneous oxidative damage to DNA?

A

Base excision repair

161
Q

What is the function of PARP?

A

Poly(ADP)-ribose polymerase catalyzes an intermediate step preceding DNA synth during base excision repair or repair of ssDNA breaks

162
Q

What are the 4 steps in nucleotide excision repair?

A

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
Q

Which DNA repair pathway is responsible for the repair of 6,4-photoproducts?

A

nucleotide excision repair (specifically global genome repair)

164
Q

Patients with xeroderma pigmentosum and Cockayne syndrome have deficiencies in which DNA repair pathway?

A

nucleotide excision repair

165
Q

How does NER differ from MMR and BER?

A

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
Q

By which NER pathway - global genome repair or transcription-coupled repair - are cyclobutane pyrimidine dimers (CPDs) most efficiently repaired?

A

transcription-coupled repair

167
Q

In which phases of the cell cycle can homologous recombination repair of ds DNA breaks occur?

A

S-phase and G2 - requires presence of homologous template (ie sister chromatid)

168
Q

In which DNA repair pathway do BRCA1 and BRCA2 participate?

A

homologous recombination

169
Q

In which DNA repair pathway is ATM active?

A

NHEJ

170
Q

Which dsDNA break repair pathway is most error-prone?

A

NHEJ - usually results in insertion or deletion of a few bp at the break site during modification of DNA to produce ligatable ends

171
Q

What type of DNA lesion does the Fanconi anemia pathway repair?

A

Interstrand crosslinks

172
Q

What steps occur following recognition of an interstrand crosslink by FANCM?

A

recruits FA-core complex, coordinates downstream function of nucleases (ie FAN1), DNApol, NER components, and BRCA-mediates HR to restart the replication fork

173
Q

Which proteins are responsible for sensing DNA DSBs and participating in cell cycle delay?

A

ATM, ATR, and DNA-PKs

174
Q

Is an ATM dimer active or inactive?

A

Inactive –> activated by autophosphorylation of monomers in the presence of DNA damage

175
Q

Which cell cycle regulators activate CHK1 and CHK2 in response to DNA damage?

A

ATM and ATR phosphorylate CHK1 and CHK2, leading to p53- and p21-dependent cell cycle arrest or apoptosis

176
Q

Is TERT considered an oncogene?

A

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
Q

How does global hypomethylation contribute to genomic instability?

A

methylation of transposable DNA elements is thought to block their activation and movement, maintaining chromosomal stability. loss of methylation –> loss of stability

178
Q

What role do MYC family proteins play?

A

Global transcription factors - thought to regulate ~15% of human genes

179
Q

What is unique about the activation of ERBB2 (HER2)?

A

Requires dimerization with other family members, cannot bind ligand itself

180
Q

What pathway is most prominently activated by mutant EGFR receptors?

A

MAPK, PI3K

181
Q

What does the PI3KCA gene encode?

A

p110 catalytic subunit of PI3K

182
Q

What are the components of the PI3K pathway?

A

PI3K converts PIP2–>PIP3 –> activates AKT –> activates mTOR

183
Q

Activation of the PI3K/AKT pathway results in silencing of which proteins?

A

GSK-3
MDM2
BAD

184
Q

What are the components of the MAPK pathway?

A

RAS –> RAF (ie BRAF) –> MEK –> ERK

185
Q

Is a cell with a BRAF mutation also likely to harbor a RAS mutation?

A

No – mutations in RAS and RAF proteins are mutually exclusive

186
Q

IDH1 and 2 were identified as oncogenes by genomic methods. What is the mechanism by which they contribute to tumorigenesis?

A

Unknown

187
Q

What tumor suppressor gene is mutated in hamartoma syndromes?

A

PTEN

188
Q

In which DNA repair pathway is RAD51 involved?

A

HR (ds break repair)

189
Q

Are BRCA1/2 oncogenes or tumor suppressor genes?

A

tumor suppressor

190
Q

Name 2 families of CDK-inhibiting proteins?

A

INK4
CIP/KIP

others: MYT1 and WEE1

191
Q

How are CDKs regulated to block cell cycle progression?

A

Ubiquitinated and degraded

192
Q

What role does APC/C play in cell cycle progression?

A

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
Q

Characterize the activity of APC/C and CDK1/2 during G1 phase?

A

High APC/C activity
Low CDK1/2 activity

also high: CDK4/6

194
Q

When does CyclinA/CDK2 activity rise, and what does it trigger?

A

G1/S

triggers DNA replication

195
Q

Which CDK-cyclin complex increases in activity in late G2? What does this initiate?

A

CyclinB-CDK1

triggers mitosis

196
Q

When are CyclinB, Polo-like kinase, and the aurora kinases activated, and what do they regulate?

A

initiated in G2/M or prophase

orchestrate early events of mitosis - shaping mitotic spindle and aligning chromatid pairs

197
Q

What molecular events drive the progression of late anaphase and telophase?

A

loss of phosphorylation of CyclinB, PLK1, and aurora kinases

increased APC/C activity

198
Q 
Which one of the BCL proteins is pro-apoptotic?
BCL-2
BCL-XL
BCL-Xs
BCL-W
A

BCL-Xs

199
Q

Are the following proteins anti-apoptotic or pro-apoptotic? BIK, BIM, BID, PUMA

A

pro-apoptotic

200
Q

Which proteins combine to form the apoptosome?

A

Cyt-c + APAF-1 + CASP9 (initiator caspase)

201
Q

Which caspases are initiator caspases?

A

Caspase 2, 8, and 9

202
Q

What are the IAPs and how do they function?

A

IAPs = inhibitors of apoptosis
ex: survivan, XIAP, IAP1/2
bind to caspases and inhibit function

203
Q

What superfamily do the death receptors FAS, TNFR1, and DR3-6 belong to?

A

TNF receptor superfamily

204
Q

What enzyme can be used as a marker of senscence?

A

B-galactosidase

205
Q

Which initiator caspase is activated by extrinsic death signals?

A

Casp8

206
Q

What cellular process is Beclin-1 required for?

A

Autophagy

207
Q

Which chromosomal abnormality would indicate telomere failure?

A

End-to-end fusions

208
Q

Name 3 inhibitors of angiogenesis.

A

Thrombospondin-1
Angiostatin (fragments of plasmin)
Endostatin (fragments of type 18 collagen)

209
Q

Following radiation-induced cell damage, is H2AX likely to be phosphorylated or unphosphorylated?

A

following DNA damage, ATM phosphorylates H2AX, which is then activated an localizes to sites of DNA ds breaks

210
Q

What affect does MDM2 have on p53?

A

ubiquitin ligase that targets p53 for degradation

211
Q

What affect do ATM and Chk2 have on p53?

A

Phosphorylate and stabilize p53

212
Q

What affect does p53 have on p21?

A

p53 increases expression of p21, which prevents Rb phosphorylation and cell cycle progression

213
Q

What does the shoulder region on a radiation survival curve represent?

A

non-lethal damage repair (ie B component)

214
Q

What is the significance of N-cadherin expression?

A

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
Q

What are the 6 classic hallmarks of cancer?

A 
Sustaining proliferative signaling
Evading growth suppressors
Enabling replicative immortality
Activating invasion and metastasis
Inducing angiogenesis
Resisting death
216
Q

What ion acts as a cofactor for MMPs?

A

Zinc

217
Q

What is uPAR?

A

urokinase type plasminogen activating receptor (serine protease)

218
Q

What are TIMPs?

A

Tissue inhibitors of metalloproteinases

219
Q

What are focal adhesion plaques?

A

anchor points between integrins and the ECM

220
Q

Which binds larger molecules: MHC class I or class II?

A

Class II - larger binding cleft

The binding cleft is the site of greatest diversity

221
Q

Which APCs are capable of activating naive T-cells?

A

Dendritic cells

222
Q

What is CD28 and what are its ligands?

A

CD28= T-cell activating costimulatory receptor
ligands = CD80, CD86
results in IL-2 production

223
Q

Is a viral infection more likely to induce a Th1 or Th2 response?

A

Th1 - drives a primarily CTL/CD8+ response

224
Q

Is a bacterial infection more likely to induce a Th1 or Th2 response?

A

Th2 - drives humoral immunity

225
Q

Which cytokines are produced by Th1 cells?

A

IL-2, IL-12
TNFa
IFNg

226
Q

What is the primary cytokine produce by Th2 cells?

A

IL-4

227
Q

What does CTLA-4 do?

A

accumulates CD80/CD86, activates IDO and inhibits T cell proliferation and signaling

228
Q

Where are PDL1 and PDL2 expressed?

A

PDL1 - many tissues

PDL2 - primarily APCs

229
Q

What does PD-1 do?

A

blocks function and survival of effector T cells

230
Q

Which cells can impart anergy on mature T-cells once they have left the thymus?

A

Dendritic cells

231
Q

Are T-regs antigen specific?

A

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
Q

What do tolerogenic DCs do?

A

Secrete TGF-B, thereby inducing Tregs

233
Q

How does IDO inhibit T cell proliferation?

A

Depletion of tryptophan

234
Q

How should monoclonal antibodies be engineered to best harness ADCC?

A

-select those Abs that bind well to activating FcRs and poorly to inhibitory receptors such as FcgIIB

235
Q

Which small molecule inhibitor is a substrate for ABCG2/BCRP?

A

gefitinib

236
Q

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?

A

CDK inhibitor

phosphorylates Rb

237
Q

Tumor suppressor gene silencing is often achieved by both promoter methylation and histone deacetylation. Are HDACi’s alone sufficient in reversing gene silencing?

A

No, both demethylation and HDACi must be achieved to reactivate genes

238
Q

What is the MOA of bortezomib?

A

Proteasome inhibitor –> induces apoptosis thru death effector caspase activation, upregulates p53, p21, Rb

239
Q

What is the HUMARA assay?

A

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
Q

Differentiate M1 and M2 macrophages in terms of cytokines produced and impact on tumors.

A

M1 –> IL-12, anti-tumor

M2 –> IL-10, promote tumor progression

241
Q

Is NFkB pro- or anti-inflammatory?

A

Pro-inflammatory, also contributes to tumor progression.

242
Q

Is NFkB pro- or anti-inflammatory?

A

Pro-inflammatory, also contributes to tumor progression.

243
Q

What is the function of p16?

A

CDK 4/6 inhibitor

244
Q

What is the function of p21/Waf-1?

A

universal CDK inhibitor (exc CDK 2 and 4)

245
Q

How is the canonical Wnt pathway activated, and what impact does this have on B-catenin?

A

binding of Wnt ligand to Frizzled
Inhibits B-catenin phosphorylation and breakdown
B-catenin translocates to nucleus and interacts with DNA binding proteins

246
Q

Which of the Wnt pathways is B-catenin independent?

A

Non-cannonical Wnt

May antagonize B catenin signaling

247
Q

What family of transcription factors is activated by B-catenin signaling?

A

T-cell factor/lymphoid enhancer factor (Tcf/Lef)

248
Q

When the null hypothesis is false and you fail to reject it, you make a type ? error. How can this be avoided?

A

Type II error = false +

Solution = larger sample size

249
Q

When the null hypothesis is true and you reject it, you make a type ? error. How can this be avoided?

A

Type I error = false -

solution = lower alpha (limit of significance)

250
Q

How does Annexin V detect apoptosis?

A

Binds phosphatidyl serine translocated to outer membrane

251
Q

What is TERT, and what % of canine tumors express TERT?

A

telomerase reverse transcriptase

>90%

252
Q

What is phospho-H2AX a marker for?

A

DNA DSBs

253
Q

What are cathepsins?

A

proteases

254
Q

What is the minimum # of patients in a Phase II trial required to detect efficacy (25% response rate)?

A

9

255
Q

What is Myc?

A

transcription factor that plays a role in cell cycle progression, apoptosis and cellular transformation

256
Q

On which cells are PD-1 and CTLA-4 expressed?

A

PD-1: activated T cells, B cells, and macrophages

CTLA-4: upregulated on activated T cells, constitutively expressed on T regs

257
Q

What are the functions of PD-1?

A

Inhibits TCR signaling
Inhibits T cell proliferation
Inhibits induction of cytokines (IFNg, IL-2, TNFa)

258
Q

Where are the 2 ligands for PD-1 expressed?

A

PDL-1 - inducible in many tissues

PDL-2 - macrophages and dendritic cells

259
Q

What type of kinases are RAF proteins?

A

serine/threonine

activated by RAS

260
Q

What do RAF proteins activate?

A

MEK –> MAPK

261
Q

Where are matrix-binding areas located on normal epithelial cells?

A

basal aspect

mesenchymal polarity is reversed, allowing migration

262
Q

What are the 3 types of EMT?

A

Type I - embryogenesis/organ development
Type II - fibrosis
Type III - metastasis

263
Q

What molecular events denote Mesenchymal to Epithelial transition once cells reach a site of colonization?

A

upregulation of E-cadherin and B-catenin

264
Q

What causes telomeric attrition?

A

inability of DNA machinery to efficiently replicate 5’ ends of linear chromosomes

265
Q

How long are human, canine, and murine telomeres?

A

human - 10-15kbp
canine - 12-23kbp (similar)
mouse - 40-60kbp (4-6X as long as humans)

266
Q

Which species are more likely to express somatic telomerase: human, dog, mouse, chicken

A

mouse and chicken

Onco Board Review (6 decks)

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