lecture 6 Flashcards
What is an E3 ubiquitin ligase?
A protein that facilitates the attachment of ubiquitin chains to a target protein.
Name three pathways that respond to environmental challenges like DNA damage or hypoxia.
NF-κB, p53, and HIF pathways.
Define hypoxia.
A condition where oxygen concentrations are lower than normal levels cells are exposed to, e.g., less than 20.9% O2 at sea level.
How do cells respond to hypoxia?
By altering chromatin structure, initiating transcriptional programs, translational blocks, microRNA changes, and DNA replication blocks.
What is the HIF system, and what does it regulate?
Hypoxia-Inducible Factor (HIF) is a transcription factor regulating oxygen homeostasis and cellular responses to low oxygen levels.
What are the key structural domains of HIF-1α?
bHLH (DNA binding), PAS, ODD (oxygen-dependent degradation domain), NTAD, CTAD, and NLS (nuclear localization signal).
How is HIF-1α regulated under normoxia?
Proline hydroxylases (PHDs) hydroxylate HIF-1α, leading to its ubiquitination by VHL and subsequent degradation in the proteasome.
Name some HIF-1α target genes involved in cellular metabolism.
Glucose transporters (GLUT1, GLUT3), phosphofructokinase, and enolase.
What is the primary role of p53 in the cell?
It acts as a tumour suppressor, regulating cell cycle arrest, DNA repair, and apoptosis.
How is p53 regulated by Mdm2?
Mdm2 ubiquitinates p53, leading to its degradation in the proteasome, maintaining low p53 levels in undamaged cells.
What happens to p53 in response to DNA damage?
Phosphorylation disrupts its interaction with Mdm2, stabilizing p53 and allowing activation of its target genes.
Explain the negative feedback loop involving p53 and Mdm2.
p53 induces the expression of Mdm2, which in turn inhibits and degrades p53 to regulate its activity.
How do hypoxia and cancer relate?
Hypoxic conditions in tumours activate HIF, promoting angiogenesis, increased glycolysis, and tumour survival.
What is Li-Fraumeni syndrome?
A hereditary cancer predisposition syndrome caused by mutations in the TP53 gene, leading to increased cancer risk.
What role does NF-κB play in cell stress response?
It is activated by degradation of its inhibitor IκBα and regulates genes involved in immune responses and inflammation.
Compare NF-κB, p53, and HIF regulation.
NF-κB activation involves inhibitor degradation, whereas p53 and HIF are continuously degraded and stabilized only upon activation.
What is the function of proline hydroxylases (PHDs) in hypoxia?
They regulate HIF by hydroxylating it under normoxic conditions, leading to HIF degradation.
What is the role of ARF in regulating p53?
ARF inhibits Mdm2, preventing p53 degradation and allowing it to act as a tumour suppressor.
What is the significance of studying hypoxia?
Hypoxia plays a role in various physiological processes and is linked to diseases like cancer, stroke, and chronic conditions.
How does hypoxia contribute to metabolic adaptation in cancer cells?
It induces glycolysis and angiogenesis, helping tumour cells survive in low oxygen environments.
