Zusammenfassung
The hypoxia-inducible factor-1 (HIF-1), which consists of the constitutive HIF-1 beta and the oxygen-responsive HIF-1 alpha subunit, is the master activator of the cellular transcriptional response to hypoxia coordinating gene expression during reduced oxygen tension. Overexpression of HIF-1 and increased transcriptional activity induced by hypoxia are linked to progression of many tumour types ...
Zusammenfassung
The hypoxia-inducible factor-1 (HIF-1), which consists of the constitutive HIF-1 beta and the oxygen-responsive HIF-1 alpha subunit, is the master activator of the cellular transcriptional response to hypoxia coordinating gene expression during reduced oxygen tension. Overexpression of HIF-1 and increased transcriptional activity induced by hypoxia are linked to progression of many tumour types such as head and neck cancer, cervical carcinoma, leukaemia and renal cell carcinoma. In this study, we demonstrate that HIF activity is increased in malignant melanoma cells already under normoxic conditions in contrast to other tumour types. HIF-1 alpha and -2 alpha knockdown by siRNA transfection revealed that this effect is due to constitutive HIF-1 alpha expression. Furthermore, the inhibition or activation of reactive oxygen species (ROS) decreased or activated, respectively, HIF-1 activity and HIF-1 alpha protein expression. Interestingly, the inhibition of the NFkappaB pathway also reduced the accumulation of HIF-1 alpha assuming a context between ROS and NFkappaB, and suggesting that ROS and NFkappaB activity contribute to HIF-1 alpha accumulation. In summary, we identified an increased HIF-1 alpha protein expression and activity in melanoma under normoxia mediated by ROS and the NFkappaB pathway. (C) 2010 Elsevier Ltd. All rights reserved.
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