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Molecular recognition > Cytokines and Growth Factors > Flashcards

Cytokines and Growth Factors Flashcards

1
Q

what is EPO produced by ?

A

Peritubular Interstitial Fibroblasts

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2
Q

what are cytokines?

A
  • small proteins 5-20 kDa
  • released by cells
  • affect other cells
  • especially important for cells of the immune system
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3
Q

how many cytokines do we know of?

A

> 50

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4
Q

what are the four distinct structural families of cytokines?

A
  • TNF tumor necrosis factor
  • interferon
  • chemokines
  • hematopoeitin
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5
Q

what are some principles for tumour necrosis factor type interactions?

A
  • a trimeric receptor and a trimeric ligand
  • ligands are beta strand type ptoteins
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6
Q

what are some priniciples of inteferon (IFNy)?

A
  • alpha helical ligand and binds to beta type receptor in similar way
  • dimeric interferon binds to dimeric receptor
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7
Q

what are some principles of chemokines?

A
  • structure includes alpha helices and beta strands
  • can be monomeric or dimeric
  • found in cosmetics and facial creams and wound healing
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8
Q

what are some priniciples of EPO hematopoetin?

A
  • Erythropoietin
  • erythrocytes are red blood cells
  • two receptors one EPO
  • EPO make RBCs
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9
Q

what does expression of a cognate receptor mean?

A

Its how a cell asks to be able to recieve signal from the blood

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10
Q

what does cytokine response (specifically EPO) depend on ?

A
  • expression of a cognate receptor

Cell type and development:
- chromatin structure
- constellation of transcription factors
- developmental history

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11
Q

If we have less oxygen we have…

A

more red blood cells and this decrease in oxygen is what EPO reacts to

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12
Q

what tells the body EPO is needed ?

A

Hif1a (Hypoxia Inducible Factor)

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13
Q

what do we need to raise the EPO response?

A
  • Hif
  • Transcription factor (to start transcription of EPO)
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14
Q

what is the mechanism by which hif1a is taken out of circulation and destroyed?

A

so in the presence of normal oxygen levels…
- prolyl hydroxylase hydroxylates Hif1a and marks it for ubiquitatylation/ destruction

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15
Q

what is the mechanism in hypoxic conditions using Hif1a?

A

asparagin hydroxylase hydroxylates Hif1a and its activation results in tagaet gene expression

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16
Q

what does EPO activate?

A

erythroid progenitor cells

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17
Q

what happens when EPO stimulates a Erythroid progenitor cell (CFU-E)?

A

it divides to two cells then 4, 8 , 16 etc
3-5 divisions and they slowly differentiate into red blood cells that slowly lose EPO receptors
leading to 30-100 erythroids

18
Q

how many ligands need to be occupied to get 80% of the physiological response?

A

50%

19
Q

what can be said about EPO ligand concentrations?

A

below the KdS

20
Q

how many EPO receptors does an EPC have?

A

1000

21
Q

what is a simple experiment to look at whether the patient has healthy blood ?

A

hematocrit experiment
centrifuge the blood and it will disperse into
1) RBCs
2) WBCs and platelets
3) Plasma

With men showing 41-50% RBCs
Women showing 36-44% RBCs

22
Q

what cancers can cause low hematocrit levels?

A
  • lymphoma (increased B/ T Lymphocyte WBC)
  • Hodgkin’s Lymphoma (increased lymphocyte WBC)
  • Leukemia (increased immature WBC)
  • Multiple Myeloma (increased myeloma cellls - malignant plasma cells in the bone marrow - reduces production of RBCs and other blood cells)
23
Q

why do cancers cause low hematocrit levels?

A

cancers use the blood producing stem cells on the expense of RBC production

24
Q

what diseases require the use of EPO to treat anemia?

A
  • chronic kidney disease
  • inflammatory bowel disease (Crohn’s disease and ulcer colitis)
  • Myelodysplasia (blood disorder) resulting from:
    > exposure to chemicals (benzene)
    > treatment of cancer (chemotherapy and radiation)
25
Q

If JAK is deleted from the gene pool what happens?

A

failure of development in fetal mammals

26
Q

describe a simple structure of JAK

A
  • a kinase
  • multiple domains (incl. linker, domain able to bind to the tail of the receptor and a lip domain)
  • two lobes
27
Q

Describe the JAK/ STAT pathway

A

1) cytokine binding and cytokine receptor dimerisation occurs
2) phosphorylation of associated JAK kinase - leads to activation (ATP to ADP)
3) phosphorylation of additional residues
4) recognition by inactive monomeric transcription factor STAT
5) phosphorylation and release of STAT
6) STAT dimerisation allows entry into the nucleus

28
Q

how does EPO act in three simple steps

A
  • EPO binds to the EPO-receptor
  • monomeric EPOr dimerises on EPO binding
  • this leads to activation of an associated kinase
    resulting in a conversion of extracellular signal to intracellular change
29
Q

describe structure of STAT

A

C-terminal phosphorylated by JAK, Phosphate tail of one monomer binds to SH2 domain of the other monomer to create a dimer formation

30
Q

Explain the cascade of protein-protein interactions in the JAK/ STAT pathway

A
  • EPO binds EPOr
  • dimerisation of EPOr occurs
  • activates cytosolic JAK-Kinase
  • Receptor phosphorylation
  • Receptor (P) recognised by SH2
  • Activates STAT pathway
  • Exposes NLS, pathway continues in the nucleus
31
Q

What is the short term adaptation to deactivate the EPO system?

A

removes phosphate from lip domain to inactivate the kinase
- has an SH2 domains
- activated upon binding to the c terminus
phosphotases = SHP1

32
Q

How does the cell achieve long term adapation (deactiviation) in regards to EPOr ?

A

using SOCS protein recognises SH2 domain and binds on the SH2 domain
SOCs protein has a SOCs box which attracts the E3 Ubiquitin ligase which then marks the receptor for destruction

33
Q

Name the two ways to switch off EPO’s activation through JAK/ STAT

A

1) Short term adaptation
- phosphatase SHP1 dephosphorylates JAK –> OFF
2) Long term adaptation
- SOCS –> block of SH2 binding sites
- SOCS –> targets JAK for degredation via E3

34
Q

name the four processes that JAK2 and the EPO pathway can activate

A

a) STATS (Transcriptional activation)
b) GRB2 or Shc (Ras - MAP kinase - transcriptional activation or repression)
c) Phospholipase Cy (Elevation of calcium - Transcriptional activation or repression; modification of other cellular proteins)
d)PI-3 kinase (Protein kinase B - Transcriptional activation or repression; modifications of other cellular proteins)

35
Q

what do STAT 1- 5 interact with

A

STAT-1: IFNy
STAT-1 and 2: IFNa/B
STAT-3,-5: growth hormones
STAT-4
STAT-5: EPO

36
Q

what type of interferons do virus infected cells produce?

A

Dendritic cells: IFNa
Fibroblasts: IFNb

37
Q

what two directions can type 1 interferons act after release by virus infected cells?

A

autocrine: towards the infected cell
paracrine: towards uninfected neighbours

38
Q

what do INFy do in terms of viral defence via the Jak-STAT pathway?

A

signal through the Jak-STAT pathway to produce >300 gene products, including cytokines

39
Q

what type of interferond fo T cells and NK cell produce as part of the viral defence?

A

type II INFy

40
Q

How can INFy kill virus infected cells or cancerous cells ?

A

autocrine: inhibition of virus replication, via apoptosis
paracrine: up-regulation of MHC-I and NK-cell activation

Molecular recognition (7 decks)

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