General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia.

TLDR

HIF‑1 is a hypoxia‑induced nuclear factor that binds the EPO gene enhancer and activates EPO transcription in Hep3B cells. The study demonstrates that HIF‑1 DNA‑binding activity is induced by hypoxia in diverse mammalian cell lines that do not express EPO. The HIF‑1 DNA‑binding complex and its activation mechanism are conserved in EPO‑producing and non‑EPO‑producing cells, and hypoxia drives reporter gene transcription through the EPO enhancer, which is abolished when HIF‑1 binding sites are mutated. These results show that HIF‑1 and its recognition sequence are common components of the general mammalian cellular response to hypoxia.

Abstract

Transcription of the human erythropoietin (EPO) gene is activated in Hep3B cells exposed to hypoxia. Hypoxia-inducible factor 1 (HIF-1) is a nuclear factor whose DNA binding activity is induced by hypoxia in Hep3B cells, and HIF-1 binds at a site in the EPO gene enhancer that is required for hypoxic activation of transcription. In this paper, we demonstrate that HIF-1 DNA binding activity is also induced by hypoxia in a variety of mammalian cell lines in which the EPO gene is not transcribed. The composition of the HIF-1 DNA binding complex and its isolated DNA binding subunit and the mechanism of HIF-1 activation appear to be similar or identical in EPO-producing and non-EPO-producing cells. Transcription of reporter genes containing the EPO gene enhancer is induced by hypoxia in non-EPO-producing cells and mutations that eliminate HIF-1 binding eliminate inducibility. These results provide evidence that HIF-1 and its recognition sequence are common components of a general mammalian cellular response to hypoxia.