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7.3 Hypoxia and Hypoxia-Inducible Transcription Factors
Hypoxia stabilizes hypoxia-inducible transcription factors (HIFs) HIF-1
α
and HIF-
2
(ARNT),
translocate to the nucleus and bind to specific, hypoxia response element or HRE
DNA sequences of target genes, promoting their transcription. Under room air
conditions, HIFs are hydroxylated by prolyl 4-hydoxylases (PHDs) using molec-
ular oxygen, iron (Fe 2+ ),
α
. Active HIFs are heterodimeric proteins that dimerize with HIF-1
β
α
-ketoglutarate and ascorbate as substrates or cofactors
(Fig. 7.1). Thus absence of oxygen (hypoxia), iron chelation, use of analogs
of
α
-ketoglutarate or siRNA mediated knockdown of prolyl 4-hydroxylases can
each inhibit hydroxylation of HIFs (Fig. 7.1) [6, 39, 65]. Hydroxylation of pro-
line residues P402 and P562 of human HIF-1
) tags
it for pVHL (von Hippel-Lindau tumor suppressor gene product) binding, ubiq-
α
(P405 and P531 of HIF-2
α
Fe 2+ , Ascorbate , O 2 ,
-ketoglutarate
PHDs
(Prolyl 4-hydroxylases)
Hypoxia/DFO/
DMOG/CoCl 2
siRNA-PHDs/
siRNA-VHL
Proline
hydroxylation
HIFs
Stabilization
pVHL binding
Ubiquitination
HIF-1
HIF-2
26S proteosomal
degradation
VEGF
VEGFR2
A 2B receptor
A 2A receptor
Angiogenesis
(New blood vessel formation)
Fig. 7.1 Schematic model of hypoxia-induced pathways leading to angiogenic responses in
endothelial cells. Under normal physiological conditions, hypoxia-inducible transcription factors,
HIF-1
are degraded through a series of steps, starting with hydroxylation of the
transcription factor by prolyl 4-hydroxylases (PHDs). This degradation pathway leading to desta-
bilization of HIFs has a negative effect on angiogenesis. On the other hand, inhibiting PHD activity
using DFO, DMOG, hypoxia or siRNA-mediated knockdown of the enzyme can stabilize HIFs.
Inhibiting the binding of pVHL to the hydroxylated HIFs using CoCl 2 or siRNA-mediated knock-
down of VHL can also stabilize HIFs. Both HIF-1 α and HIF-2 α regulate vascular growth by
common as well as unique pathways. VEGF-VEGFR2 pathway is a known inducer of angiogen-
esis and is regulated both by HIF-1 α and HIF-2 α in endothelial cells. Adenosine A 2A and A 2B
receptors are also known to promote angiogenesis (or new blood vessel formation). While HIF-
1
α
and HIF-2
α
α
regulates expression of A 2A receptor in human lung microvascular endothelial cells. DFO: desfer-
rioxamine (Iron chelator); DMOG: dimethyloxalylglycine (analog of
α
regulates expression of A 2B receptor in human dermal microvascular endothelial cells, HIF-2
α
-ketoglutarate); pVHL (von
Hippel-Lindau tumor suppressor gene product)
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