The Role of the HIF-1α Transcription Factor in Increased Cell Division at Physiological Oxygen Tensions

HIF-1 is a transcription factor that mediates the cellular responses to low oxygen environments, mainly as a result of having an oxygen-labile subunit, HIF-1 alpha. HIF-1 alpha has been carefully studied in the context of severe hypoxic stresses (<1% O-2), but it is also known to be present at oxygen tensions commonly found in normal tissues in vivo (similar to 1-13% O-2), albeit at much lower levels. Its role under these physiological conditions is not fully understood. Here, we show that a transcriptionally active HIF-1 alpha was up-regulated at 5% O-2, both in normal and cancer cells, but only some of its target genes were elevated as a result. HIF-1 alpha induction was in part dependent on the activation of the ERK1/2 MAPK signalling pathway, which we have previously shown is active at 5% O-2. We also found that HIF-1 alpha does not contribute to the protection against DNA damage that can be observed in low oxygen environments, and that there are certain DNA damaging agents, such as doxorubicin and actinomycin D, that prevent HIF-1 alpha induction independently of p53. Moreover, absence of HIF-1 alpha significantly reduced the growth advantage of cells cultured at 5% O-2. In view of these data, we conclude that HIF-1 alpha can be induced and activated at physiological oxygen tensions in a MAPK-dependent manner and that, although this does not lead to pro-survival responses to stress, it determines the increased cell proliferation rates that are common under these conditions.