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

Test 3: 44-45 Flashcards

(73 cards)

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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
MAPK leads to :
nucleotide synthesis, gene expression, protein synthesis, cell growth MAPK is created by active RAS→ RAF→ MEK→ MAPK
26
Growth factor also stimulate phospholipids by
PI3K Phosphoinositide 3-kinases used to make phospholipids which are used to activate kinase by unmasking kinase domain or change confirmation of kinase domain
27
full pathway of RTK
**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
28
how to deactivate MAPK
**MKP-1 (MAP Kinase Phosphatase)**
29
how to deactivate RAF → MEK
**RKIP (Raf Kinase Inhibitor Protein: disrupts Raf-MEK interaction)**
30
how to deactivate RAS
**Ras GTPase Activity**
31
how to stop RTK
**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
mutation in GAP can create \_\_\_
neurofibromatosis Ras can deactivate, always on, always sending signal to divide
33
mutations in Ras lead to ___ % of cancers
20-30% Ras stays active, cell will continuously grow and divide
34
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.
**Noonan Disease:** Mutation in the **Sos or Raf genes.** Proteins stay active longer than normal disrupting normal development.
35
**Noonan Disease:**
Mutation in the **Sos or Raf genes.** Proteins stay active longer than normal disrupting normal development. ## Footnote 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
**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?**
Cancer: Ras is mutated in 20-30% of all cancers
37
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 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
A point mutation causing a change from **valine to glutamic** acid at amino acid 450 causes what? and why
mutation in B**RAF which** leads to **prostatic carcinoma**
39
what is an alternate way to activate RAS pathway instead of RTK
integrins interact with fibronectin
40
Jak STAT pathway
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
The ___ pathway is disrupted in many **hemapotoietic cancers**
Jak-STAT
42
mutation in ___ **which** leads to **prostatic carcinoma**
B**RAF**
43
TGF beta SMAD pathway
**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
\_\_\_ hold kinase in place/ together
scaffold proteins help with amplification and efficiency
45
receptor tyrosine kinase has three parts
outside of cell-where growth factors bind transmembrane intracellular- conformational change which activates tyrosine kinase protein which leads to **phosphorylation of tyrosine**
46
explain RTK
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
Raf→ Mek→ MAPK are all \_\_\_
serine/threonine kinase will give phosphate to eachother
48
RAS binds to cell membrane with the help of \_\_\_
Farnesyl and Farnesyl Transferase
49
Farnesyl is ___ and likes to be where in the cell
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
how to stop Ras from binding to Farnesyl
**CAAX** 4 amino acid inhibitor protein cistine - 2 hydrophobic amino acids and any amino acid
51
how to kill mutated RAS
trigger RAS into inactive RAS then inhibit SOS from activating iRAS back into aRAS
52
what drug to to stop kinase
Gleevec (Imatinib)
53
The tumor sample was subjected to DNA sequence analysis. **Mutations in c-kit Exon 11 were found.** What will you do?
Treat with imatinib (gleevac) stops kinase activity
54
explain angiogenesis therapy for cancer
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
3 steps of wound healing
**Inflammation** **Proliferative Granulation tissue formation** **Matrix formation and remodeling**
56
**Thrombin causes release of ___ from platelet alpha granules.**
**TGF-b, PDGF, FGF** **chemofactors that attract fibroblasts, macrophages, neutrophils, and keratinocytes**
57
**Thrombin causes the release of chemofactors such as TGF-b, PDGF, FGF that attract \_\_\_**
**fibroblasts, macrophages, neutrophils, and keratinocytes**
58
**Cell migration during wound healing cause the release of ___ from the extracellular matrix**
**growth factors**
59
**\_\_\_ begin to remove debris.**
**Macrophages**
60
granulation of tissue during wound healing :
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
TGF-b and PDGF attract fibroblasts to wound site. They become ___ which aid in wound closure.
myofibroblasts (will squeeze wound shut)
62
Matrix formation and remodeling during wound healing:
1. Gradual dissolution of granulation tissue. 2. Formation of **scar tissue.** 3. Scar not as good as normal tissue.
63
**if you add ___ to surface wounds and burns, would healing will increase 2 fold**
EGF
64
if you add ___ and ___ to incisions wound healing will improve
TGFB and PDGF
65
why don't fetuses scar
decrease in TFG beta = slower healing, normal skin forms instead of scar
66
\_\_\_ can be added to help with impaired wound healing such as chemotherapy
TGF beta, PDGF, EGF
67
\_\_ or __ can be used to improve angiogenesis
TGF beta and FGF VEGF
68
when stimulated a 7 alpha helical transmembrane receptor will most likely interact with \_\_\_
trimeric G protein
69
You patient has a defect in the GTPase activating protein (GAP). What will be the most likely affect?
Ras will remain in the GTP bound state
70
Why does RAS associated with the cell membrane
post translational farnesylation
71
When a growth factor binds to its receptor, what usually occurs on its internal cytoplasmic domain?
specific tyrosines are phosphorylated
72
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?
MAP kinase inhibitor
73
Why is gleevac a useful drug for treatment of some malignancies?
it blocks the ATP binding sit on the Abl kinase

21 fall: Biochem (44 decks)

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