S1. HIF and Oxygen Sensing Flashcards
(41 cards)
What experiment first demonstrated a ‘humoral’ factor inducing erythropoiesis?
Blood from hypoxic/anaemic rabbits was transferred into normal rabbits, causing erythrocytosis in the latter
What discovery linked hypoxia to erythropoiesis?
The identification of the Erythropoietin (EPO) gene, showing EPO production is induced under hypoxic conditions
How was the EPO-producing cell type identified in the kidney?
Using transgenic mouse models expressing tagged EPO, identifying interstitial fibroblasts as the producers
Which cell lines enabled molecular dissection of the HIF pathway?
Hep3B and HepG2 hepatoma cell lines, which showed hypoxic EPO induction
What region of the EPO gene is critical for hypoxic regulation?
The Hypoxia Response Element (HRE) adjacent to the EPO gene
How was HIF first identified?
By analyzing proteins binding to the HRE, leading to the discovery of HIF as a heterodimer of alpha and beta subunits
What mutation analysis helped explain HIF regulation by oxygen?
Mutations in the oxygen-dependent degradation domain (ODDD) showed its importance for HIF stabilization in hypoxia
What role does the nematode C. elegans play in HIF research?
It helped identify Egl-9, the prolyl hydroxylase responsible for HIF regulation, due to its simpler genetic system
How do PHD enzymes regulate HIF?
They hydroxylate prolines on HIF-alpha in normoxia, marking it for degradation by VHL
What is the role of FIH in HIF regulation?
FIH hydroxylates asparagine residues on HIF-alpha, preventing co-activator binding and limiting transcription in normoxia
What distinguishes HIF-1alpha and HIF-2alpha?
HIF-1alpha is ubiquitous and essential for embryonic development, while HIF-2alpha specializes in adult hypoxic responses like erythropoiesis
What experiment showed HIF-2alpha’s role in erythropoiesis?
Transgenic mice lacking HIF-2alpha failed to show hypoxia-induced erythropoiesis
How is the carotid body involved in hypoxia responses?
It senses arterial oxygen drops, triggering acute ventilatory responses through Type I cell neurotransmitter release
What role does HIF-2alpha play in the carotid body?
It mediates chronic hypoxia-induced carotid body proliferation and ventilatory acclimatization
What is the link between VHL mutations and cancer?
VHL mutations lead to constitutive HIF activation, promoting tumors like renal clear cell carcinoma
How do high-altitude populations demonstrate adaptation to hypoxia?
Genetic studies reveal SNPs in HIF-2alpha and PHD2, associated with reduced erythrocytosis and pulmonary hypertension
What are PHIs and their clinical significance?
Prolyl hydroxylase inhibitors enhance erythropoiesis and are used to treat renal anemia, with potential for other ischemic conditions
What is the mechanism of action for HIF-2alpha antagonists?
They block dimerization of HIF-2alpha with HIF-beta, inhibiting its transcriptional activity
How did experiments with reporter constructs demonstrate HIF ubiquity?
Transfection of HRE-reporter genes into various cell types showed hypoxia responsiveness across diverse tissues
What experiment linked mitochondrial adaptations to HIF-2alpha?
HIF-2alpha was shown to induce atypical mitochondrial subunits like Cox4i2, enhancing oxygen sensing under hypoxia
How might HIF pathways impact COVID-19?
PHIs activating HIF-1alpha impair SARS-CoV-2 infection and replication, suggesting therapeutic potential
What does the term ‘pseudohypoxia’ describe?
Constitutive activation of HIF due to mutations, mimicking hypoxic conditions
What is the role of angiogenesis in hypoxia adaptation?
It involves the formation of new blood vessels, mediated by HIF-induced VEGF expression, to enhance oxygen delivery
Which tumors are commonly associated with VHL mutations?
Renal clear cell carcinomas, hemangioblastomas, and pheochromocytomas
