Author/Editor		Huang, L Eric; Ho, Vincent; Arany, Zoltan; Krainc, Dimitri; Galson, Deborah; Tendler, Drory; Livingston, David M; Bunn, H Franklin
Title		Erythropoietin gene regulation depends on heme-dependent oxygen sensing and assembly of interacting transcription factors
Type		članek
Source		Kidney Int
Vol. and No.		Letnik 51, št. 2
Publication year		1997
Volume		str. 548-52
Language		eng
Abstract		Studies on erythropoietin (Epo) gene expression have been useful in investigating the mechanism by which cells and tissues sense hypoxia. Both in vivo and in Hep3B cells. Epo production is induced not only by hypoxia but also by certain transition metal (cobalt and nickel) and by iron chelation. When Hep3B cells were incubated in an iron deficient medium, Epo mRNA expression was enhanced fourfold compared to Hep3B cells in iron enriched medium. Epo induction by cobalt was inversely related to iron concentration in the medium, indicating competition between the two metals. Under hyperbaric oxygen, cobalt induction of erythropoietin mRNA was modestly suppressed while nickel induction was markedly enhanced. These recent observations support the proposal that the oxygen sensor is a heme protein in which cobalt and nickel can substitute for iron in the porphyrin ring. The up-regulation of Epo gene transcription by hypoxia depends on at least two known DNA binding transcription factors, HIF-1 and HNF-4, which bind to cognate response elements in a critical approximately 50 bp 3' enhancer. Hypoxia induces HIF-1 binding. HNF-4, an orphan nuclear receptor constitutively expressed in kidney and liver, binds downstream of HIF-1 and cooperates with HIF-1, contributing importantly to high level and perhaps tissue specific expression. The C-terminal activation domain of HNF-4 binds to the beta subunit of HIF-1. The C-terminal portion of the alpha subunit of HIF-1 binds specifically to p300, a general transcriptional activator. Hypoxic induction of the endogenous Epo gene in Hep3B cells as well as an Epo-reporter gene was fully inhibited by E1A, an adenovirus protein that binds to and inactivates p300, but only slightly by a mutant E1A that fails to bind to p300. Moreover, overexpression of p300 enhanced hypoxic induction. (Abs. trunc. at 2000 ch.)
Descriptors		GENE EXPRESSION REGULATION CELL HYPOXIA CELL LINE DNA-BINDING PROTEINS ERYTHROPOIETIN HEME MODELS, BIOLOGICAL NUCLEAR PROTEINS OXYGEN PHOSPHOPROTEINS PROTEIN CONFORMATION RNA, MESSENGER SIGNAL TRANSDUCTION TRANSCRIPTION FACTORS