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Medicine Unit 2 > Cell proliferation > Flashcards

Cell proliferation Flashcards

1
Q

what is cell proliferation

A

increase in cell number

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2
Q

what is cell proliferation essential for

A

tissue homeostasis

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3
Q

what else is tissue homeostasis dependent on

A

the apoptotic pathway operating correctly

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4
Q

what can deregulation in cell proliferation or apoptosis result in

A

diseases such as cancers and neurodegeneration

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5
Q

what are mitogens

A

growth factors or cytokines with the potential to active cell cycle

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6
Q

what does the mitogenic signal cause

A

the cell to synthesise proteins in order to overcome the restriction point (“R” point)

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7
Q

what is the restriction point

A

acts as a cellular brake to block cells from advancing from G1 phase to S phase

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8
Q

what regulates cell proliferation

A

MAPK signalling
Mitogen Activated Protein Kinase
the cascade have 3 component structures

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9
Q

ERK signalling pathway

A

caused by growth factors
Raf, MEK, ERK
leads to cell growth and cell division

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10
Q

p38 signalling pathway

A

caused by cytokines, osmotic stress and DNA damage
TAK, MKK3, p38
leads to inflammation apoptosis

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11
Q

JNK signalling pathway

A

caused by cytokines, osmotic stress and DNA damage
ASK,MKK4, JNK
leads to inflammation apoptosis

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12
Q

what do mitogens signal to

A

cell surface receptors such as members of the receptor tyrosine kinase family

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13
Q

what do tyrosine kinases do

A

phosphorylate tyrosine residues on target proteins

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14
Q

how many receptor tyrosine kinases and how many classes

A

50 RTK into 20 different classes each with multiple members

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15
Q

activation of receptor tyrosine kinase signalling

A

signalling molecules bind to the receptor
receptor dimerise and kinase activity is stimulated
auto phosphorylation and trans-phosphorylation of tyrosines
phosphorylated sites allow other proteins to dock to which in turn activates them

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16
Q

which receptor tyrosine kinases are part of the ErbB family

A

HER1, HER2, HER3 and HER4

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17
Q

erbB1

A

known as HER1 or EGFR (epidermal growth factor receptor)
has a tyrosine kinase domain which is intracellular
membrane between
then extracellular receptor domain
associated with EGF, TGF alpha and amphiregulin ligands

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18
Q

erbB2

A

known as HER2 or neu
has an intracellular tyrosine kinase domain
membrane between
not associated with any specific ligands

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19
Q

erbB3

A

known as HER3
same structure as others except no tyrosine kinase domain
associated with heregulins ligand

20
Q

erbB4

A

known as HER4
has a tyrosine kinase domain
same structure as others
associated with NRG2, NRG3 and heregulins ligands

21
Q

what is dimerisation critical for

A

signal specificity
signal activity (HER2:HER3)
redundancy

22
Q

homodimers of ErbB receptors

A

HER1:HER1
HER2:HER2
HER3:HER3
HER4:HER4

23
Q

problem with HER2:HER2 homodimerisation

A

no specific ligands
lack of specific homodimer function

24
Q

problem with HER3:HER3 homodimerisation

A

no tyrosine kinase domain
lack of specific homodimer function

25
Q

what does the activation of EGFR cause

A

downstream Ras signalling

26
Q

process of EGFR activation

A

causes adaptor protein like Grb2 to bind first
enables other proteins to bind to GRb2 to come closer to p-EGFR
SOS can bind to GRb2 and allows it to be activated by p-EGFR
SOS activation allows Ras activation and ERK signalling is activated

27
Q

in how many cancers is Ras mutated

A

30%

28
Q

what is Ras

A

G-protein similar to G alpha subunit of heterotrimeric G-protein coupled receptor
small GTPase
SOS functions as a guanine exchange factor (GEF)

29
Q

when is Ras inactive

A

when bound to GDP
GTP-ase activating proteins stimulate Ras to hydrolyse GTP thereby inactivating itself

30
Q

when is Ras active

A

when bound to GTP
GEF stimulates Ras to replace the bound GDP in exchange of GTP

31
Q

process of activated Ras

A

binds to Raf which is a serine/threonine kinase and is activated by autophosphorylation
Raf phosphorylates MEK
MEK is activated
MEK phosphorylates ERK (MEK very specific to ERK to ensure signal specificity)
ERK is activated

32
Q

what is the significance of ERK activation

A

ERKs phosphorylate many nuclear and cytoplasmic proteins such as transcription factors c-Jun and c-fos
allows ERKs to regulate cell proliferation, differentiation, migration, inhibition of apoptosis

33
Q

in cell proliferation what can ERKs induce

A

Myc
is a transcription factor
activates transcription of necessary genes to allow cells to pass the R-point

34
Q

how can cells regulate proliferation

A

turn off proliferative signalling
get destroyed when signalling becomes excessive (induce apoptosis)

35
Q

two ways that ERK signalling can be turned off

A

prevent release of EGF
inactivate EGFR

36
Q

preventing the release of EGF

A

target metalloproteinases
EGF is normally synthesised as a transmembrane protein which is leaved by metalloproteinaes during cell proliferation

37
Q

inactivating EGFR

A

remove the receptor
EGFR is internalised via endocytosis and sent to lysosomes for destruction

38
Q

what causes constant proliferation signalling to ERK

A

deregulation of endoscope -> increased EGFR levels
over activation of metalloproteinase -> increase EGF levels
over expression of EGFR -> increased signalling
mutation in kinase domain -> always active
deletion of ligands binding domain EGFR variant III -> always active

39
Q

what are the three mechanisms to target EGFR

A
  1. EGFR receptor inhibitors
  2. EGFR dimerisation inhibitors
  3. Tyrosine kinase inhibitors
40
Q

name the EGFR receptor inhibitors

A

cetuximab
matuzumab
nimotuzumab
panitumumab

41
Q

name EGFR dimerisation inhibitors

A

trastuzumab
pertuzuzmab
both HER2 inhibitors

42
Q

tyrosine kinase inhibitors

A

gefitinib
erlotinib
lapatinib

43
Q

mechanisms for resistance to EGFR inhibitors in non small cell lung carcinomas

A

bypass mechanisms
EGFR alterations

44
Q

bypass mechanism examples

A

HER2 amplification
B-RAF mutations
met amplification
PI3K signalling
small cell lung carcinoma

45
Q

EGFR alteration examples

A

T790M mutation (largest cause for resistance)
EGFR T790M amplification

46
Q

Ras cancer mutations

A

mutated Ras can’t be inactivated by GTPase-activating proteins GAPs
Ras remains bound to GTP

47
Q

B-Raf in cancer

A

mutated in 7% of all cancers
frequently mutation is V600E (valine to glutamic acid)
mutation increases the kinase activity by 500-fold

Medicine Unit 2 (28 decks)

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