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PCL386 > Term Test 1 > Flashcards

Term Test 1 Flashcards

1
Q

Receptor activation of MAPK pathway

A

EGF binds to EGFR cause receptor dimerization and autophosphorylation on cytosolic tyrosines

GRB2 binds to phosphotyrosine via SH2 (also have SH3) domain

SOS1 (GEF) bind to membrane complex

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2
Q

3 key RAS protein in humans

A

KRAS (Kirsten sarcoma virus)
HRAS (Harvey sarcoma virus)
NRAS (neuroblastoma RAS)\

function as binary molecular switch

“off” binds to GDP
“on” binds to GTP

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3
Q

What facilitates RAS activation?

A

SOS (GEF) turn GDP to GTP in RAS (activate)

RAS-GAP turn GTP to GDP (inactivate)

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4
Q

2 RAS effector protein

A

PI3K and RAF (Rapidly accelerated fibrosarcoma) leads to proliferation

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5
Q

Three distinct RAF proteins

A

A-RAF
B-RAF
C-RAF

activated RAF is a phosphorylated dimer

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6
Q

Downstream of RAF signalling

A

RAF (BRAF most active, CRAF then ARAF) kinase activates MEK1 and MEK2

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7
Q

What does MEK1/2 phosphorylate?

A

ERK1 and ERK2 (extracellular signal-regulated kinases)

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8
Q

ERK kinase

A

ERK kinase then dimerizes and enters the nucleus

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9
Q

Scaffold protein (KSR1)

A

maintain three sequential acting kinases as a function complex

RAS -> RAF -> MEK -> ERK

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10
Q

3 downstream effect of ERK1/2

A
  1. proliferation transcription factors
  2. MKs (MAPK-activated protein kinases)
  3. Negative regulators of the MAP kinase pathway (MKP) or (DUSP)
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11
Q

4 transcription factors from ERK

A
  1. Myc (oncogene) activates growth (repress negative regulators of cell cycle and p53)
  2. FOS-JUN (cell proliferation and differentiation)
  3. ETS
  4. FOXO family (induction of apoptosis, p21, p27)
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12
Q

Mutations in MAP kinase pathway

A

KRAS, HRAS, NRAS (colorectal, non-small cell lung, pancreatic, breast cancer)

BRAF (activating oncogenic mutations V600E)

MEK and ERK not mutated

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13
Q

RAS mutation and hotspots

A

maintained in active form (GTP-bound)

hotspots G12, G13, Q61

pancreatic and colorectal cancer

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14
Q

RAF mutations

A

BRAF
mutationally active
expressed in melanoma, glioblastoma, thyroid, lung and colon cancers

V600E substitution of glutamic acid for valine at amino acid 600
mimics phosphorylation (constitutively active kinase activity)
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15
Q

Farnesyl Transferase Inhibitor (FTI)

A

inhibit RAS function

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16
Q

Sorafenib

A

First RAF inhibitor to gain regulatory approval, multi-targeted kinase inhibitor

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17
Q

Vemurafenib

A

BRAF (V600E) selective inhibitor

Resistance to BRAF inhibitors can occur through activating mutations of MEK1/2

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18
Q

MEK inhibitors

A

Trametinhib GSK1120212

use in combination with BRAF inhibitors to treat melanomas

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19
Q

Rapamycin

A

macrolide antibiotic
immunosuppressive
anticancer

inhibit mTOR

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20
Q

mTOR

A

serine/threonine kinase

PI3K related kinase family

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21
Q

4 common mTOR components

A
  1. catalytic mTOR subunit
  2. mammalian lethal with sec-13 protein 8 (mLST8)
  3. DEP domain containing mTOR-interacting protein (DEPTOR)
  4. Tti1/Tel2 complex
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22
Q

2 mTORC1-specific components

A

Raptor

PRAS40

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23
Q

3 mTORC2 specific components

A
  1. Rapamycin insensitive companion of mTOR (Rictor)
  2. mammalian stress-activated map kinase-interacting protein 1 (mSin1)
  3. protein observed with rictor 1 and 2 (protor1/2)
24
Q

Signalling upstream of mTOR

A

TSC1/TSC2
heterodimer
GTPase activating protein (GAP) for RHEB GTPase

25
Q

RHEB

A

GTP (active)
GDP (inactive)

GTP-bound form directly interacts with mTORC1 and stimulates its kinase activity

TSC1/2 negatively regulates mTORC1 by converting RHEB-GTP to GDP

26
Q

PI3K regulation on mTORC1

A

AKT phosphorylation inhibits TSC2 and can also activate mTORC1 independently by phosphorylating PRAS40 to cause its dissociation

27
Q

ERK1/2 regulation on mTORC1

A

ERK1/2 can inhibit TSC1/2 by phosphorylating TSC2

28
Q

AMPK

A

energy sensor
response to hypoxia or low energy state

phosphorylates TSC2 increase activity (activating phosphorylation)
phosphorylates Raptor, allosteric inhibition of mTORC1

29
Q

Hypoxia sensor

A

DNA damage response 1 (REDD1)

activates TSC2 function

30
Q

DNA damage sensor

A

P53

induce expression of TSC2 and PTEN, cause down-regulation of entire PI3K-mTORC1 axis.

31
Q

Protein Translation control downstream of mTOR

A

initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1)
S6 kinase 1 (S6K1)
phosphorylation promotes protein synthesis

32
Q

4EBP1

A

phosphorylation of 4E-BP1 by mTORC1 prevent its binding to eIF4E
eIF4E move on to exert effect
initiate cap-dependent translation

Protein translation and synthesis

33
Q

S6K1

A

phosphorylation increase mRNA biogenesis, translational initiation and elongation

34
Q

SREBP1 and 2

A

lipogenesis
mTORC1 inhibition reduce SREBP1 and 2 expression
lowers expression of lipogenic genes

35
Q

mTORC1 and autophagy

A

mTORC1 block autophagy, promotes growth

directly phosphorylates and suppress ULK1/Atg13/FIP200 to block autophagy

36
Q

mTORC2

A

activates AKT by phosphorylating Ser473

respond to growth factors such as insulin
require PI3K

37
Q

mTORC1 in cancer

A

mTORC1 is hyperactivated in up to 70% of all human tumors

support cancer growth
synthesis of protein
angiogenesis
nutrient uptake
metabolism
38
Q

3 key proteins regulated by mTOR activation

A
  1. Cell cycle regulators
  2. Proangiogenic factors
  3. Amino acid and glucose transporters
39
Q

Angiogenesis by mTOR

A

activation elevates synthesis of HIF-1a and HIF-2a

HIF turns on hypoxic stress genes including VEGF and PDGF-B

cancer cells secret proangiogenic factors, promote new vessels

40
Q

mTOR in nutrient uptake

A

mTOR activation increase expression of nutrient transporters
LAT and GLUT1

cancer cell can access to nutrients and metabolic fuel support unregulated growth

41
Q

Rapamycin inhibition of mTOR

A

forms a gain of function complex with FKBP12

this complex is an allosteric inhibitor of mTOR

42
Q

Rapalogs

A

Rapamycin derivatives
only modest efficacy in tumors

negative feedback loops in mTOR contribute to limit therapeutic efficacy for rapalogs

BINDS TO FKBP12 and allosteric inhibition

43
Q

S6K-IRS feedback

A

rapalogs block feedback to turn off PI3K signalling and AKT
Rapalogs activate AKT pathway

not effective in mTORC2
only destabilize mTORC1

44
Q

Dual mTOR-PI3K inhibition

A

inhibit mTORC1, mTORC2 and class I PI3K
decrease phosphorylation of AKT, S6K1 and 4E-BP1
may hurt normal cells

NOVARTIS, EXELIXIS

45
Q

Limitations of Dual mTOR-PI3K inhibition

A

lack of biomarkers
need better understanding of molecular mechanism
selection of drug combination therapies
more effective and personalized cancer therapy

46
Q

2 frequent mutations of PIK3CA

A

E535K
H1047R

Leads to increase PIP3 levels

47
Q

Warburg’s effect

A

Tumor cells convert most of their glucose to lactate even in the presence of adequate oxygen
aerobic glycolysis
make 4 molecules of ATP for every molecule of glucose consumed

metabolism is different in cancer cells
tumor cells undergoing rapid growth use glucose extremely inefficiently

48
Q

First step of glycolysis by AKT

A

Phosphorylate AS160 promotes translocation of vesicles contain GLUT4 to cell surface

GLUT4 allows entry of glucose

49
Q

How does PDK1 controls pyruvate entry?

A

PDK1 phosphorylate PDH
PDH cant turn pyruvate into Acetyl-CoA
Acetyl-CoA cant go into TCA
pyruvate become lactate

“Warburg kinase”

50
Q

Anaplerosis

A

Metabolic pathway used to generate other molecules (replenish TCA intermediates)

51
Q

Glutaminolysis by MYC

A

MYC increase glutamine transporter SLC1A5

MYC increase first enzyme (GLS) in glutamine metabolism

GLS turns glutamine into glutamic acid

52
Q

MYC in glycolysis

A

makes GLUT1
Lactate dehydrogenase
Hexokinase

53
Q

Extracellular Acidification Rate (ECAR)

A

lactate production

54
Q

Oxygen consumption rate (OCR)

A

mitochondrial oxidative phosphorylation

55
Q

Gas-Chromatography/ Mass Spectrometry (GS/MS)

A

allows us to track where heavy carbons end up

56
Q

Isocitrate dehydrogenase 1 (IDH1)

A

can produce oncometabolites (2-hydroxyglutarate) in IDH mutants

IDH mutant cells have a hypermethylation phenotype which blocks DNA

DNA differentiation block + proliferation = cancer

57
Q

Nutlins

A

inhibit p53-MDM2 binding

only works on tumor that contains normal or wildtype p53

PCL386 (12 decks)

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