lecture 6 Flashcards
define hypoxia
the lowering of oxygen concentrations compared to the normal level cells are exposed to / sea level ±20.9%
What happens to cells if the O2 levels are wrong?
they undergo stress as theyre not used to dealing with those conditions
What medical conditions are due to hypoxia?
high altitude disease, stroke/ischemia, diabetes, chronic kidney disease, gastrointestinal disease, schizophrenia, neurodegenerative, ageing, rheumatoid arthritis, cance
Did COVID cause hypoxia?
80% mild cases
15% severe disease
5% critical disease with respiratory failure
what happens in cell as result of hypoxia?
translational block
microRNA
DNA replication block
transcriptional program
chromatin structure changed
What is the action of cells to reverse hypoxia?
restoration of oxygen homeostasis
cell survival
cell death
what is HIF?
hypoxia inducible factor - a heterodimeric transcription factors: HIF-α, HIF-1α, HIF-2α, HIF-3α and HIF-1β
Where is HIF-1α expressed?
ubiquitously expressed in all tissues
Which HIF have restricted expression?
HIF-2α and HIF-3α to certain tissues only
How is HIF-3α different to the other HIF-α?
lacks C-terminus transactivation domain
functions as a dominant negative inhibitor for HIF-1α and HIF-2α
able to active a different set of genes in hypoxia
How do HIF-α differ if structure to HIF-β?
HIF-β doesn’t contain an ODD (oxygen dependent degradation domain)/NTAD
Why is HIF continually degraded?
as to turn on the HIF pathway you need to block the degradation step
How is HIF-α regulated in normoxia?
proline hydroxylases (PHDs), FIH (factor inhibiting HIF - an asparagine hydroxylases) enzymes use O2 to hydroxylate key residues within the HIF-1α subunit
Hydroxylation of the ODD signals for VHL (Von Hippel Lindau - a ubiquitin E3 ligase) binding and ubiquitination occurs leading to proteasomal degradation
How is HIF-1α regulated in hypoxia?
PHDs and FIH are inhibited, and HIF-1α is stabilised and able to dimerize with HIF-1β and activate target gene transcription through recruitment of coactivators
What makes up the structure of p53 tumour suppressor?
Transactivation domain,
proline rich domain,
nuclear localisation sequence,
tetramerisation domain
What are the positive and negative effects of p53?
:)
tumour suppression, development, stem cell modulation, fertility
:(
ischemia, treacher collins syndrome, neurodegeneration, aging
What regulates p53?
its inhibitor MDM2
What is the role of p53?
Pushes cell into cycle arrest to promote DNA repair and allow the cell cycle to restart
OR
Trigger apoptosis for death and elimination of damaged cells
What is the role of Mdm2?
promotes ubiquitination of p53 leading to its degradation by the proteasome keeping p53 levels low in undamaged cells
Describe the action of Mdm2 to activate p53 in response to DNA damage?
In response to DNA damage p53 becomes phosphorylates at serine 15 by the ATM or ATR kinases
Mdm2 is phosphorylated disrupting interaction between p53 and Mdm2 stimulating negative feedback loop with Mdm2 gene expression limiting p53 activation
What is the role of ARF?
p14 ARF stops oncogene activation by disrupting interaction between p53 and Mdm2 - tumour suppression
Results in increased levels of transcriptionally active p53
How can cancer cells inhibit p53?
Viral infection - interrupting ubiquitin E6
Mutation - stops ARF, ATM, p53
Amplification - Mdm2
What is Li-Fraumeni syndrome?
hereditary cancer syndrome
early cancer diagnosis (before 30)
what causes Li-fraumeni syndrome?
-hereditory genetic condition
-caused by mutation in TP53
-takes away genes ability to function correctly
