The regulation of GRP78 and messenger RNA levels by hypoxia is modulated by protein kinase C activators and inhibitors
- Stanford Univ. School of Medicine, CA (United States)
In this study, we have shown that steady-state levels of glucose-regulated 78 kDa (GRP78) protein and messenger RNA increase during a 5-h exposure to 0.02% oxygen. This increase in GRP78 protein and mRNA induced by hypoxia can be abolished by a 1-h pretreatment of cells before hypoxia with the protein kinase C (PKC) inhibitors staurosporine and H7 at concentrations at which the drugs themselves do not cause cytotoxicity. Although all studies using protein kinase inhibitors must be interpreted with caution, staurosporine and H7 have been shown to be potent inhibitors of PKC activity, suggesting a role for PKC in mediating the transcriptional regulation of GRP78 by hypoxia. Further support for PKC in regulating GRP78 gene expression by hypoxia stems from gel-mobility shift studies in mixtures of nuclear extracts from aerobic or hypoxic cells with a 36 bp region of the GRP78 promoter (-170 to -135). Binding of this factor could be inhibited by pretreating cells with the PKC inhibitor staurosporine before hypoxia or activated by treating cells with the PKC-activating phorbol ester TPA. These data suggest that activation of this hypoxia-responsive factor is sensitive to oxygen levels and seems to be mediated through a PKC signal transduction pathway. 13 refs., 4 figs.
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 56768
- Report Number(s):
- CONF-9305202--; CNN: Grant CA03353
- Journal Information:
- Radiation Research, Journal Name: Radiation Research Journal Issue: 1 Vol. 138; ISSN 0033-7587; ISSN RAREAE
- Country of Publication:
- United States
- Language:
- English
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