Cell proliferation

Question 1

what is cell proliferation

Answer 1

increase in cell number

Question 2

what is cell proliferation essential for

Answer 2

tissue homeostasis

Question 3

what else is tissue homeostasis dependent on

Answer 3

the apoptotic pathway operating correctly

Question 4

what can deregulation in cell proliferation or apoptosis result in

Answer 4

diseases such as cancers and neurodegeneration

Question 5

what are mitogens

Answer 5

growth factors or cytokines with the potential to active cell cycle

Question 6

what does the mitogenic signal cause

Answer 6

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

Question 7

what is the restriction point

Answer 7

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

Question 8

what regulates cell proliferation

Answer 8

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

Question 9

ERK signalling pathway

Answer 9

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

Question 10

p38 signalling pathway

Answer 10

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

Question 11

JNK signalling pathway

Answer 11

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

Question 12

what do mitogens signal to

Answer 12

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

Question 13

what do tyrosine kinases do

Answer 13

phosphorylate tyrosine residues on target proteins

Question 14

how many receptor tyrosine kinases and how many classes

Answer 14

50 RTK into 20 different classes each with multiple members

Question 15

activation of receptor tyrosine kinase signalling

Answer 15

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

Question 16

which receptor tyrosine kinases are part of the ErbB family

Answer 16

HER1, HER2, HER3 and HER4

Question 17

erbB1

Answer 17

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

Question 18

erbB2

Answer 18

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

Question 19

erbB3

Answer 19

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

Question 20

erbB4

Answer 20

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

Question 21

what is dimerisation critical for

Answer 21

signal specificity
signal activity (HER2:HER3)
redundancy

Question 22

homodimers of ErbB receptors

Answer 22

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

Question 23

problem with HER2:HER2 homodimerisation

Answer 23

no specific ligands
lack of specific homodimer function

Question 24

problem with HER3:HER3 homodimerisation

Answer 24

no tyrosine kinase domain
lack of specific homodimer function

Question 25

what does the activation of EGFR cause

Answer 25

downstream Ras signalling

Question 26

process of EGFR activation

Answer 26

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

Question 27

in how many cancers is Ras mutated

Answer 27

30%

Question 28

what is Ras

Answer 28

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

Question 29

when is Ras inactive

Answer 29

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

Question 30

when is Ras active

Answer 30

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

Question 31

process of activated Ras

Answer 31

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

Question 32

what is the significance of ERK activation

Answer 32

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

Question 33

in cell proliferation what can ERKs induce

Answer 33

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

Question 34

how can cells regulate proliferation

Answer 34

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

Question 35

two ways that ERK signalling can be turned off

Answer 35

prevent release of EGF inactivate EGFR

Question 36

preventing the release of EGF

Answer 36

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

Question 37

inactivating EGFR

Answer 37

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

Question 38

what causes constant proliferation signalling to ERK

Answer 38

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

Question 39

what are the three mechanisms to target EGFR

Answer 39

1. EGFR receptor inhibitors 2. EGFR dimerisation inhibitors 3. Tyrosine kinase inhibitors

Question 40

name the EGFR receptor inhibitors

Answer 40

cetuximab matuzumab nimotuzumab panitumumab

Question 41

name EGFR dimerisation inhibitors

Answer 41

trastuzumab pertuzuzmab both HER2 inhibitors

Question 42

tyrosine kinase inhibitors

Answer 42

gefitinib erlotinib lapatinib

Question 43

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

Answer 43

bypass mechanisms EGFR alterations

Question 44

bypass mechanism examples

Answer 44

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

Question 45

EGFR alteration examples

Answer 45

T790M mutation (largest cause for resistance) EGFR T790M amplification

Question 46

Ras cancer mutations

Answer 46

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

Question 47

B-Raf in cancer

Answer 47

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