Cells exposed to
hypoxia increase their synthesis of a specific set of
proteins called
oxygen regulated proteins. Recently, three of these
proteins have been identified as hemoxygenase,
Glucose Regulated
Protein 78 kilodaltons and
Glucose Regulated Protein 94 kilodaltons. In contrast, reoxygenation from hypoxic conditions increases the synthesis of the
heat shock proteins. Although the molecular signals required for regulation of both sets of
proteins by
hypoxia and reoxygenation are still under investigation, it is known that their expression is regulated at the transcriptional level. This finding suggests that these stresses work either singularly or together to control the activation of nuclear
transcription factors which bind distinct regulatory sequences in the promoter region of these genes. One possible nuclear
transcription factor which could act as a transcriptional regulator for both
hypoxia and reoxygenation gene transcription is the
heat shock transcription factor. In this report, we focused on the kinetics of HSF activation by
hypoxia in normal and tumor cell lines of murine and human origins. In cell culture, both the normal diploid cell line AG1522 and the tumor cell line JSQ-3 possess the same kinetics of HSF activation (binding to the heat shock
element) by
hypoxia, with maximal induction at or after 3 hr. We have also shown that the activation of HSF occurs in the SCCVII
tumor in vivo without clamping, but not in SCCVII cells grown in monolayers. When SCCVII
tumors are dissociated and allowed to reoxygenate in cell culture, HSF binding decreased in 5 hr, and was undetectable after 18 hr. Furthermore, one human
tumor biopsy tested for the presence of
hypoxia by both the pO2 histograph (Eppendorf, Germany) and HSF binding showed good agreement for both techniques. These results suggest that HSF binding may be a useful marker for monitoring the tumor hypoxia.