Regulation of erythropoietin gene expression.

The study of erythropoietin gene expression provides a paradigm for understanding gene regulation in response to hypoxia. The sensor for detecting alterations in oxygen tension appears to be a heme protein. Ongoing transcription and protein synthesis are necessary for hypoxic induction of erythropoietin messenger RNA. In the past few years, considerable progress has been made in the identification and characterization of cis-acting elements and trans-acting factors that contribute to erythropoietin gene expression. The erythropoietin promoter and 3' enhancer function synergistically in response to hypoxia. Whereas hypoxia-inducible factor 1 specifically binds to the 3' enhancer conferring hypoxic induction, hepatic nuclear factor 4 interacts with the promoter as well as the 3' enhancer for stimulus- and tissue-specific induction of the erythropoietin gene. In addition, a segment in the 3' untranslated region contributes to the relatively rapid turnover of erythropoietin messenger RNA.