The study by Wang and Semenza investigates the role of hypoxia-inducible factor 1 (HIF-1) in the transcriptional response to hypoxia. They demonstrate that HIF-1, a nuclear factor with DNA binding activity, is induced by hypoxia in various mammalian cell lines, even those where the erythropoietin (EPO) gene is not transcribed. HIF-1 binds to a specific site in the EPO gene enhancer, which is essential for hypoxic activation of transcription. The composition of the HIF-1 DNA binding complex and its isolated subunit are 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 render the enhancer noninducible. These findings suggest that HIF-1 and its recognition sequence are common components of a general mammalian cellular response to hypoxia. The study also explores the mechanism of HIF-1 activation, including its induction by cobalt chloride and heat shock, and the role of de novo protein synthesis in this process. The results provide evidence for the widespread involvement of HIF-1 in hypoxic activation of gene transcription across different cell types.The study by Wang and Semenza investigates the role of hypoxia-inducible factor 1 (HIF-1) in the transcriptional response to hypoxia. They demonstrate that HIF-1, a nuclear factor with DNA binding activity, is induced by hypoxia in various mammalian cell lines, even those where the erythropoietin (EPO) gene is not transcribed. HIF-1 binds to a specific site in the EPO gene enhancer, which is essential for hypoxic activation of transcription. The composition of the HIF-1 DNA binding complex and its isolated subunit are 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 render the enhancer noninducible. These findings suggest that HIF-1 and its recognition sequence are common components of a general mammalian cellular response to hypoxia. The study also explores the mechanism of HIF-1 activation, including its induction by cobalt chloride and heat shock, and the role of de novo protein synthesis in this process. The results provide evidence for the widespread involvement of HIF-1 in hypoxic activation of gene transcription across different cell types.