lecture 6 - HIF and p53 Flashcards
what protein facilitates the attachment of ubiquitin chains to target protein
E3 ubiquitin ligase
what is hypoxia
lowering of the oxygen concentrations compared to the normal levels cells are exposed to
anoxia is the
absence of oxygen completely
as a tumor grows the core becomes hypoxic the tumor then initiates
the hypoxia response
3 cellular responses to hypoxia
restoration of oxygen homeostasis
cell survival
cell death
HIF system
hypoxia inducible factor
HIF is a heterodimeric transcription factor
HIF-alpha and HIF-1beta
3 alpha subunits (1alpha, 2alpha, 3 alpha)
HIF-1alpha: expressed in all tissues
HIF structure
helix-loop-helix: mediates DNA binding
C-terminal transactivation domain (CTAD): allows them to activate transcription
key thing they have which allows them to repond to oxygen levels is
ODD (oxygen dependent degradation) domain
HIG-1beta doesnt have an
ODD domain
HIF-1alpha regulation at normal levels of oxygen
PHD (proline hydroxylase) mediate hydroxylation (add OH) of HIF-1a at at proline residues in the ODD domain
hydroxylated prolines allow recruitment of
VHL (Von Hippel Lindau protein) which is an E3 ubiquitin ligase which stimulates ubuiqitination of HIF-1a and degrades it
HIF-1a is being made continuously by the cell but its also being
continuously degraded
if O2 levels drop the PHD and FIH cant function as
they require the oxygen in order to induce the hydroxylated so HIF-1a stabilises and can carry out its functions
FIH (factor inhibiting HIF) hydroxylases an asparagine domain in the CTAD this
inhibits transcriptional activity
VHL binds to
hydroxylates prolines
when HIF-1a is stabilised is dimerizes with HIF-1b
dimer is the active transcription factor
CTAD isnt hydroxylated by FIH so it can bind to
p300/CBP do activator proteins to regulate transcription
HIF controls many targets
oxygen supply
transcription
cellular metabolism
cell growth/death
HIF control
p53 (tumour suppressor and transcription factor) functions as a
tetramer
p53 responds to DNA damage
normally its inactive and bound to inhibitor mdm2
if the cell recieves a DNA damage stimulus mdm2 becomes
inactivated and p53 becomes active
primary response of p53 is to induce
cell cycle arrest:
cell stops proliferating and allows a chance for the DNA repair and the the cell cycle restarts
