The HIF pathway Flashcards
how is hypoxia defined as
lowering of the O2 conc compared to sea level (20.9)
what are the medical relevance of hypoxia
High altitude disease, Stroke/ ischemia, Diabetes, chronic kidney disease, GI disease, Cancer, Rheumatoid arthritis, Ageing, Neurodegenerative disease, Schizophrenia
how do cells react to low O2 (5)
Translational block
Transcriptional program
Chromatin structure changes
DNA replication block
MicroRNA signature
what are the cellular responses to hypoxia
Restoration of oxygen homeostasis
Cell survival
Cell death
What is the HIF system
Hypoxia Inducible Factor system
what are the 4 types of HIF and what are they
- a hetero-dimeric transcription factor
-HIF 1a, 2a and 3a
-HIF-1B
what is the difference between expression locations of HIF-a and there functions
1α- ubiquitously expressed in all tissues
2α- expression restricted to certain tissues
3α- expression restricted to certain tissues and lacks C-terminus transactivation domain. Functions as a dominant negative inhibitor for HIF-1α and HIF-2α.
How is HIF-1a regulated in normoxia
- Proline hydroxylases (PHDs) and FIH (factor inhibiting HIF) enzyme use O2 to hydroxylate key residues with the HIF-1a subunit
- Hydroxykation of the ODD signals for VHL (Von Hippel Lindau)
what do all HIF-a have incommon
ODD = oxygen dependent degradation domain
what are Von Hippel Lindau protein
a ubiquitin E3 ligase
When VHL binds to the ODD on HIF-1a, what occurs
leads to proteasomal degradation
what occurs to HIF-1a in hypoxia
- PHDs and FIH are inhibited
- HIF-1a is stabilised and able to dimerise with HIF-1B and activate target gene transcription through recruitment of co-activators
what is the co-activator recruited when dimerisation occurs
p300/CBP
What are the 6 types of HIF targets
Oxygen supply, Transcription, cellular metabolism, cell growth, HIF control and cell death
