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21 fall: Biochem > Test 3: 44-45 > Flashcards

Test 3: 44-45 Flashcards

1
Q

Your patient has a single amino acid change in the Ras gene. This mutation leads to a reduction in the GTPase function of Ras. Is this a problem? What disease does your patient most likely suffer from?

A

Cancer: Ras is mutated in 20-30% of all cancers

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2
Q

Your canine patient has prostatic carcinoma. From the deep recesses of your vet school memory, you decide to sequence the B-RAF gene exon 15. What are you looking for?

A

A point mutation causing a change from valine to

glutamic acid at amino acid 450

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3
Q

Your patient has pulmonary valve stenosis and atrial septal defects and hypertrophic cardiomyopathy, short stature, learning problems, impaired blood clotting, and a characteristic configuration of facial features including a webbed neck and a flat nose bridge.

A

Noonan Disease: Mutation in the Sos gene

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4
Q

Your patient is an 11-year-old spayed female mongrel dog weighing 14.1 kg and with bilateral mandibular lymph node metastases from a mast cell tumor. The primary tumor on the muzzle had been completely resected by the referring veterinarian 1 month previously. Initial examination revealed bilateral enlarged mandibular lymph nodes measuring 2.2 × 1.8 × 1.5 cm on the left and approximately 1 cm on the right. No relapse was detected on the muzzle. Cytological examination of the enlarged mandibular lymph nodes by aspiration biopsy showed metastatic tumor cells. Although chemotherapy was initiated with concurrent administration of intravenous vinblastine at 2 mg/m2 weekly and oral prednisolone at 10–15 mg/day, the lymph node lesions progressed rapidly. The tumor sample was subjected to DNA sequence analysis. Mutations in c-kit Exon 11 were found. What will you do?

A

Tr eat with imatinib

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5
Q

What are some growth factors?

A

Small Peptides (EGF, TGFa, TGFb, FGF)

Insulin (Insulin-like growth factors)

Steroids (dexamethasone, hydrocortisone)

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6
Q

what are some functions of growth factors

A

Cell Proliferation

Cellular Differentiation

Extracellular Matrix Formation

Cell Secretion

Cell Motility

Morphogens during Development

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7
Q

when do growth factors function

A

will trigger a cell in G0 or G1 phase and trigger cell to go through one round of cell cycle (proliferation and division)

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8
Q

How do growth factors work in general?

A

GF binds to type of receptor with an intercellular and extracellular component

these receptors live on cell surface and will convert extracellular contact to intracellular signal

The receptor-growth factor complex does not need to come into the cell to work

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9
Q

3 types of growth factor receptors

A

tyrosine kinase (sometimes serine)

7 alpha helical (7TM, GPCR)

steroid receptors

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10
Q

RTK pathway overview

A

RTK: tyrosine kinase

adapter protein

monomeric G proteins

serine/threonine kinases

transcription factors

gene regulation

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11
Q

7 alpha helical pathway overview

A

7 alpha helical (GPCR)

trimeric G proteins

cyclic nucleotides

membrane channels

membrane signals

gene regulation

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12
Q

Binding of growth factor to receptor causes

A

Binding to its Receptor

Often results in receptor dimerization

Causes conformational change in the receptor

This change leads to kinase activation

Receptor cytoplasmic domain is phosphorylated

Now the internal cytoplasmic domain must interact with other proteins to send the signal

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13
Q

what protein interacts with the activated RTK receptor

A

RTK binds with growth factor, dimerizes, changes shape and becomes phosphorylated

GRB2 binds (type of adapter protein)

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14
Q

protein domains

SH2, PTB

A

interact with phosphotyrosine (p-Tyr)

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15
Q

which protein domain interacts with p-Tyr

A

p-Tyr= phosphotyrosine

SH2, PTB

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16
Q

protein domains

SH3, WW

A

interact with certain configurations of proline

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17
Q

what type of protein domains interact with interact with certain configurations of proline

A

SH3 and WW

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18
Q

protein domains

PDZ

A

hydrophobic interactions

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19
Q

what type of protein domains interact with hydrophobic interactions

A

PDZ

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20
Q

protein domain

PH

FYVE

A

interact with phospholipid interactions

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21
Q

what type of protein domains interact with interact with phospholipid interactions

A

PH FYVE

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22
Q

explain how GRB2 works

A

adapter protein with 2 SH3 and 1 SH2 domains, loosely binded to Sos

SH2 domain will attach to p-Tyr= phosphotyrosine

SH3 domains bind to proline

once SH2 binds to pTyr of receptor GRB2 will strongly bind with Sos

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23
Q

what is Sos

A

guanine nucleotide releasing protein

Loosely attached to GRB2 in RTK (tyrosine kinase receptor)

becomes strongly attached to GRB2 when GRB2 SH2 protein domain binds to the pTyr on the RTK, this changes GRB2 and now strongly binds to Sos at GRB2 SH3 protein domain for prolines

Sos will make GDP → GTP (will let go of one guanine)

Ras will bind to GTP and becomes active

this activation of Ras will stimulate kinase cascade which will make cell divide

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24
Q

RAS activates what

A

RAF→ MEK→ MAPK/ERK

MAPK/ ERK leads to :

nucleotide synthesis, gene expression, protein synthesis, cell growth→ cell growth

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25
Q

MAPK leads to :

A

nucleotide synthesis, gene expression, protein synthesis, cell growth

MAPK is created by

active RAS→ RAF→ MEK→ MAPK

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26
Q

Growth factor also stimulate phospholipids by

A

PI3K

Phosphoinositide 3-kinases

used to make phospholipids which are used to activate kinase by unmasking kinase domain or change confirmation of kinase domain

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27
Q

full pathway of RTK

A

receptor tyrosine kinase

growth factor attaches to receptor, receptor dimerizes and phosphorylated

GRB2 binds to p-Tyr of receptor, which stimulated GRB2 to bind strongly to prolines of Sos, which will kick a guanine off GDP to create GTP which will active Ras

Ras will trigger kinase cascade

Ras→ Raf→ Mek→ MAPK = cell growth

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28
Q

how to deactivate MAPK

A

MKP-1 (MAP Kinase Phosphatase)

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29
Q

how to deactivate RAF → MEK

A

RKIP (Raf Kinase Inhibitor Protein: disrupts Raf-MEK interaction)

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30
Q

how to deactivate RAS

A

Ras GTPase Activity

31
Q

how to stop RTK

A

MKP-1 (MAP Kinase Phosphatase)

RKIP (Raf Kinase Inhibitor Protein: disrupts Raf-MEK interaction)

Ras GTPase Activity

GAP (GTPase Activating Protein)

Receptor Phosphatases

Receptor Degradation or Recycling

32
Q

mutation in GAP can create ___

A

neurofibromatosis

Ras can deactivate, always on, always sending signal to divide

33
Q

mutations in Ras lead to ___ % of cancers

A

20-30%

Ras stays active, cell will continuously grow and divide

34
Q

Your patient has pulmonary valve stenosis and atrial septal defects and hypertrophic cardiomyopathy, short stature, learning problems, impaired blood clotting, and a characteristic configuration of facial features including a webbed neck and a flat nose bridge.

A

Noonan Disease: Mutation in the Sos or Raf genes. Proteins stay active longer than normal disrupting normal development.

35
Q

Noonan Disease:

A

Mutation in the Sos or Raf genes. Proteins stay active longer than normal disrupting normal development.

Your patient has pulmonary valve stenosis and atrial septal defects and hypertrophic cardiomyopathy, short stature, learning problems, impaired blood clotting, and a characteristic configuration of facial features including a webbed neck and a flat nose bridge.

36
Q

Your patient has a single amino acid change in the Ras gene. This mutation leads to a reduction in the GTPase function of Ras. Is this a problem? What disease does you patient most likely suffer from?

A

Cancer: Ras is mutated in 20-30% of all cancers

37
Q

Your canine patient has prostatic carcinoma. From the deep recesses of your vet school memory, you decide to sequence the BRAF gene exon 15. What are you looking for?

A

A point mutation causing a change from valine to glutamic acid at amino acid 450

80% of patients will have this mutation

Can treat with imatinib?

Ras→ RAF

38
Q

A point mutation causing a change from valine to glutamic acid at amino acid 450 causes what? and why

A

mutation in BRAF which leads to prostatic carcinoma

39
Q

what is an alternate way to activate RAS pathway instead of RTK

A

integrins interact with fibronectin

40
Q

Jak STAT pathway

A

cytokines bind to Jak, Jak phosphorylates transcription factors(STAT) that sit in the cytoplasm, these will dimerize and go into nucleus and turn on genes needed for proliferation

Jak: Janus Kinase (Tyrosine kinase)

STAT: Signal Transducer of Activated Transcription

The Jak-STAT pathway is disrupted in many hemapotoietic cancers

41
Q

The ___ pathway is disrupted in many hemapotoietic cancers

A

Jak-STAT

42
Q

mutation in ___ which leads to prostatic carcinoma

A

BRAF

43
Q

TGF beta SMAD pathway

A

TGFb: Transforming Growth Factor Beta

SMAD: Mothers Against dpp

TGF beta binds to TGFbeta receptors, this causes kinase activity which will phosphorylate SMAD proteins, which will hetrodimerize and enter nucleus

44
Q

___ hold kinase in place/ together

A

scaffold proteins help with amplification and efficiency

45
Q

receptor tyrosine kinase has three parts

A

outside of cell-where growth factors bind

transmembrane

intracellular- conformational change which activates tyrosine kinase protein which leads to phosphorylation of tyrosine

46
Q

explain RTK

A

growth factors binds

transmembrane

conformational change which activates tyrosine kinase protein which leads to phosphorylation of tyrosine

adapter protein GRB2 sees this pTyr and binds

GRB2 is weakly bound to SOS until it binds to pTyr then strongly binds

SOS forces GDP to GTP which activates Ras

Ras→ Raf→ Mek→ MAPK→ (will phosphorylate proteins that lead to gene expression)

47
Q

Raf→ Mek→ MAPK are all ___

A

serine/threonine kinase

will give phosphate to eachother

48
Q

RAS binds to cell membrane with the help of ___

A

Farnesyl

and Farnesyl Transferase

49
Q

Farnesyl is ___ and likes to be where in the cell

A

hydrophobic, inside the cell membrane

will bind to RAS and drag it to cell membrane where it can be activated and trigger

RAS→ RAF→ MEK→MAPK

50
Q

how to stop Ras from binding to Farnesyl

A

CAAX

4 amino acid inhibitor protein

cistine - 2 hydrophobic amino acids and any amino acid

51
Q

how to kill mutated RAS

A

trigger RAS into inactive RAS

then inhibit SOS from activating iRAS back into aRAS

52
Q

what drug to to stop kinase

A

Gleevec (Imatinib)

53
Q

The tumor sample was subjected to DNA sequence analysis. Mutations in c-kit Exon 11 were found. What will you do?

A

Treat with imatinib (gleevac)

stops kinase activity

54
Q

explain angiogenesis therapy for cancer

A

kill healthy endothelial cells that provide blood supply to cancer

no blood supply cancer will shrink, if it regrows can treat again

effective but doesn’t help long term lifespan. leads to increase in metastasis to area with healthy blood supply

55
Q

3 steps of wound healing

A

Inflammation

Proliferative Granulation tissue formation

Matrix formation and remodeling

56
Q

Thrombin causes release of ___ from platelet alpha granules.

A

TGF-b, PDGF, FGF

chemofactors that attract fibroblasts, macrophages, neutrophils, and keratinocytes

57
Q

Thrombin causes the release of chemofactors such as TGF-b, PDGF, FGF that attract ___

A

fibroblasts, macrophages, neutrophils, and keratinocytes

58
Q

Cell migration during wound healing cause the release of ___ from the extracellular matrix

A

growth factors

59
Q

___ begin to remove debris.

A

Macrophages

60
Q

granulation of tissue during wound healing :

A
  1. Dense population of fibroblasts, macrophages, and neovasculature in loose matrix of collagen, fibronectin and hyaluronic acid.
  2. TGF-b increases expression of genes needed for extracellular matrix formation.
  3. TGF-b and PDGF attract fibroblasts to wound site. They become myofibroblasts which aid in wound closure.
61
Q

TGF-b and PDGF attract fibroblasts to wound site. They become ___ which aid in wound closure.

A

myofibroblasts (will squeeze wound shut)

62
Q

Matrix formation and remodeling during wound healing:

A
  1. Gradual dissolution of granulation tissue.
  2. Formation of scar tissue.
  3. Scar not as good as normal tissue.
63
Q

if you add ___ to surface wounds and burns, would healing will increase 2 fold

A

EGF

64
Q

if you add ___ and ___ to incisions wound healing will improve

A

TGFB and PDGF

65
Q

why don’t fetuses scar

A

decrease in TFG beta = slower healing, normal skin forms instead of scar

66
Q

___ can be added to help with impaired wound healing such as chemotherapy

A

TGF beta, PDGF, EGF

67
Q

__ or __ can be used to improve angiogenesis

A

TGF beta and FGF

VEGF

68
Q

when stimulated a 7 alpha helical transmembrane receptor will most likely interact with ___

A

trimeric G protein

69
Q

You patient has a defect in the GTPase activating protein (GAP). What will be the most likely affect?

A

Ras will remain in the GTP bound state

70
Q

Why does RAS associated with the cell membrane

A

post translational farnesylation

71
Q

When a growth factor binds to its receptor, what usually occurs on its internal cytoplasmic domain?

A

specific tyrosines are phosphorylated

72
Q

As a clinician, you have drugs that specifically inhibit the function of GRB2, RAS, growth factor receptor, SOS and MAP kinase. You patient has a defect in Raf that causes it to constitutively active. What drug do you use?

A

MAP kinase inhibitor

73
Q

Why is gleevac a useful drug for treatment of some malignancies?

A

it blocks the ATP binding sit on the Abl kinase

21 fall: Biochem (44 decks)

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