Activation of the heat shock transcription factor by hypoxia in normal and tumor cell lines in vivo and in vitro

Amato J. Giaccia, Elizabeth A. Auger, Albert Koong, David J. Terris, Andrew I. Minchinton, George M. Hahn, J. Martin Brown

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

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 SCCV1I 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.

Original languageEnglish (US)
Pages (from-to)891-897
Number of pages7
JournalInternational Journal of Radiation Oncology, Biology, Physics
Volume23
Issue number4
DOIs
StatePublished - 1992
Externally publishedYes

Keywords

  • Gel retardation assay
  • Heat shock transcription factor
  • Hypoxia

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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