Hypoxia and gene expression Flashcards
What are 6 diseases that have sustained hypoxia?
Altitude sickness
CO poisoning
Vascular disease
Stroke
Inflammation
Cancer
What is MDR1?
A chemotherapeutic resistant gene
Why are hypoxic cancer cells difficult to treat?
Far away from blood supply
Adaptive genes
What is the most common HIF target?
EPO
What is HIF?
Transcription factor that can regulate >200 genes associated with adaptation to hypoxia
What does the upregulation of HIF 1 alpha cause?
bind to promoter regions of target genes (adaptive genes)
What 4 things do adaptive genes trigger in hypoxia?
Glycolytic enzymes
Increased blood oxygenation
Increased vessel diameter
angiogensis
What are 3 genes that cause erthyropoesis?
EPO
Transferrin
Transferrin receptor
What are the 2 genes causing vasodilation?
iNOS
adrenomedullin
What 3 genes cause glycolysis?
GLUT 1 and 3
lactate dehydrogenase
phosphofructokinase
What 4 genes cause angiogenesis?
VEGF
VEGF-R
angiopoeitins
placental derived GF
What gene does HIF-1 switch in the mitochodria in hypoxia?
COX4-1 -> COX4-2 in hypoxia
What enzymes regulates HIF?
Hydroxylases at the level of accumulation & transactivation
How often is HIF mRNA made?
Constantly
What are the 2 types of hydroxylases?
PHD - adds OH to proline residues
FIH - adds OH to aspargine residues
What do the addition of OH by PHD cause?
Binding to VHL
What does VHL promote binding of?
Ub chains - promote degradation of HIF
What is FIH’s MoA in HIF activity in normoxia?
FIH uses oxygen as a substrate to asparagine to C terminal - CBP can no longer bind - no efficient transactivation of gene
What are the 3 isoforms of PHD?
PHD 1,2 and 3
What is the most important PHD for HIF?
PHD2
What are the 3 PHD substrates?
O2
Fe2+
ascorbate
How many isoforms of FIH are there?
1
What are the 3 substrates for FIH?
O2
Fe2+
ascorbate
What 2 things does HIF1alpha require to become transcriptionally active?
HIF1beta and CBP
