Hf. Bunn et al., ERYTHROPOIETIN - A MODEL SYSTEM FOR STUDYING OXYGEN-DEPENDENT GENE-REGULATION, Journal of Experimental Biology, 201(8), 1998, pp. 1197-1201
The physiological regulation of the red cell mass depends upon enhance
d transcription of the erythropoietin (Epo) gene in response to hypoxi
a, Studies of Epo gene expression have been useful in investigating th
e mechanism by which cells and tissues sense hypoxia and respond with
biologically appropriate alterations in gene expression. It is likely
that oxygen sensing involves a heme protein in which cobalt and nickel
can substitute for iron in the porphyrin ring. Indirect evidence sugg
ests that the sensor is present in all cells and is a multi-subunit as
sembly containing an NAD(P)H oxidase capable of generating peroxide an
d reactive oxygen intermediates, which serve as signaling molecules, T
he up-regulation of Epo gene transcription by hypoxia is mediated by a
t least two known DNA-binding transcription factors, hypoxia-inducible
factor 1 (HIF-1) and hepatic nuclear factor 4 (HNF-4), which bind to
cognate response elements in a critical 3' enhancer approximately 50 b
p in length. HIF-1 binding is induced by hypoxia as well as by cobalt.
The activation of HIF-1 by hypoxia depends upon the selective protect
ion of its a subunit from ubiquitin-dependent proteolysis by means of
a mechanism that involves redox chemistry and perhaps phosphorylation.
HNF-4 is an orphan nuclear receptor that is constitutively expressed
in kidney and liver and which cooperates with HIF-1 to give maximal hy
poxic induction. In hypoxic cells, p300 or a related family member for
ms a macromolecular assembly with HIF-1 and HNF-4, enabling transducti
on from the Epo 3' enhancer to the apparatus on the promoter responsib
le for the initiation of transcription.