Pathways (NF-kB, HIF, JAK/STAT, MAPK cascade, P53 ) Flashcards
NF-kB
is a dimer found in almost all animal cells, which regulates inflammation
what does activation of NF-kB cause
transcription of anti-oxidant proteins (SOD), NADPH oxidase, COX-2 and iNOS
what is NF-kB induced by
TNF-alpha, ROS, cocaine, viral and bacterial antigens
NF-kB pathway
1) signal attaches to the receptor
2) activating IKK
3) IKK phosphorylates IKBalpha (which is in complex with NF-kB)
4) Once three phosphates added to IKBalpha, it detaches from NF-kB
5) NF-kB translates to the nucleus
6) activating genes which mediate inflammation
NF-kB activates genes genes involved in
cell growth, survival, migration and angiogenesis
JAK/STAT is involved in processes such as
immunity, cell division, cell death and tumour formation
JAK/STAT receptor lacks
intrinsic tyrosine oatvity- activates janus kinase (cytosolic kinase receptor
target genes for JAK/STAT
-MYC (porto-oncogenes)
-P21
-cytokines
-iNOS
SOC (suppressor of cytokine signaling)
JAK/STAT can work to
suppress cytokine signalling via SOC
JAK/STAT pathway
1) ligand binds to receptor (EPO)
2) receptor dimerises (confomational change)
3) JAKs move closer together and phosphorylate the receptor
4) phosphorylated receptor recruits the TF STAT
5) Receptor phosphorylates STAT
6) phosphorylated STAT dislocates from the recwproe and dimerises via phosphotyrosine
7) STAT dimer is a TF
8) translocates to the nucleus and activates transcription
HIF is a
TF
in hypoxic conditions
HIF induces transcription causing angiongensis- to supply tissue with more oxygen
HIF plays a central role in
regulate of human metabolism
HIF causes an increase in
anaerobic enzymes
Normoxia
normal oxygen
-HIF degraded by hydroxylation
Hypoxia
low oxygen
- HIF not degraded
- angiogensis
Normoxia and HIF pathway
1) no shortage of O2 for proxylhydroxylate
2) HIF is hydroxylated
3) this attract E3 Ubiquitin ligase
4) HIF moves to proteasome and is degraded- therefore cannot cause transcription in the nucleus
Hypoxia and HIF pathway
1) shortage of oxygen for proxy-hydroxylate
2) therefore HIF isn’t hydroxylated
3) E3-UL is not attracted to HIF- no ubiquitination
4) HIF translocates to the nucleus
5) HIFalpha and HIFbeta forms
6) proteins transcribed which help regulate hypoxia
MAPK cascade stands for
mitogen activated protein kinases
MAPK can be
initiated by MANY PATHWAYS
what receptor does MAPK use
Tyrosine kinase
overall affect of MAPK cascade
cell survival and proliferation
MAPK cascade pathway
1) mitogen binds to RTK
2) receptor dimerzes
3) TK domain autophosphorylates
4) when phosphorylated the receptor attracts proteins with a SH2 domain (Grb2)
5) Grb2 is phosphorylated
6) sos which is attached to Grb2 is activated and phosphorylates RAS
7) RAS binds kinase RAF and activates via phosphorylation
8) MEK and ERK also phosphorylated by posh
9) ERk-P translates to the nucleus and acts as a TF
10) genes involving cell proliferation and survival
overall the MAPK cascade causes
cell proliferation and survival
order of MAPK cascade
1) Grb2 phos
2) SOS activation
3) phosphorylation of RAS by SOS
4) RAS activates RAF
5) RAF activates MEk
6) MEK activates ERK
7) ERK= TF
RAS..
RAF, MEK, ERK
P53 known as
the guardian of the genome
P53 is a
tumour suppressor TF
what does p53 regulate
inhibits cell cycle, G1/S and G2/M
MDM2
E3 ubiquitin ligase
how doe P53 inhibit cell cycle
stops cells from progressing when the cell is damaged or it will trying repair DNA
P53 in a normal cell
1) E3 ubiquity ligase (MDM2) ubiqutinates P53
2) sent for proteasomal degradation
normal cells will have …….. P53 expressed
very little- meaning mitosis can occur
P53 in cellular stress
1) cell damage/DNA damage, hypoxia- activates oncogene
2) ATM kinase activated
3) ATM-K phosphorylates CHK1/2 kinase which phosphorylates P53
4) when phosphorylated P53 is unbound to MDM2 (which would usually send it to the proteasome)
5) P53 translocates to the nucleus to act as a TF
6) Apoptosis and DNA repair
which genes do P53 transcribe
genes which cause apoptosis and DNA repair
