Frontiers in Drug Discovery

Frontiers in Drug Discovery

Volume: 1

Erythropoietic Stimulating Agents

Indexed in: EBSCO.

The development of new erythropoietic stimulating agents (ESAs) has significantly increased in recent years. Researchers are focused on different and interesting concepts, namely, methods to increase ...
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Modulation of Erythropoietin Gene Expression

Pp. 27-42 (16)

João C. Fernandes, Flávio Reis, Elísio Costa and Alice Santos-Silva

Abstract

Regulation of erythropoiesis and the maintenance of erythroid homeostasis rely on modulation of erythropoietin (EPO) gene expression in response to tissue oxygen tension. EPO expression is tightly regulated in a tissue-specific manner and by development stage. However, is the hypoxic stimulation that primarily determines the EPO transcription. A 50 bp hypoxia-inducible enhancer, located 120 bp 3′ to the polyadenylation site, mediates the transcriptional response to hypoxia by binding several stimulatory transcription factors, such as hypoxia-inducible transcription factors (HIF-1α and HIF-2α) and hepatocyte nuclear factor-4α (HNF-4 α). Pro-inflammatory cytokines, as interleukin (IL)-1β and tumour necrosis factor (TNF)-α, inhibit EPO expression, apparently by increasing the binding of GATA factors to the EPO promoter and by down-regulation of HNF-4α. Understanding oxygen and tissue-specific regulation of EPO production is of high physiologic relevance. Moreover, this knowledge might be useful for new therapies to treat clinical states associated with aberrant EPO gene expression.

Keywords:

Erythropoietin, hypoxia, gene regulation, hypoxia-inducible factor, EPO enhancer.

Affiliation:

Instituto de Biologia Molecular e Celular da Universidade do Porto, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal.