Identification of functional hypoxia response elements in the promoter region of the DEC1 and DEC2 genes.

Adaptation to hypoxia is a crucial process both physiologically (i.e. in chondrocytes) and pathologically (i.e. in tumor cells). Previous studies have shown that DEC1, a basic helix-loop-helix transcription factor, is induced by hypoxia in glioma cells (Ivanova, A. V., Ivanov, S. V., Danilkovitch-Miagkova, A., and Lerman, M. I. (2001) J. Biol. Chem. 276, 15306-15315). In the present study, we found that hypoxia or CoCl(2) enhanced the mRNA expression of DEC2, as well as DEC1, within 24 h in chondrogenic ATDC5, 293T, and HeLa cells. In luciferase assays, the regions between -524 and -401 in the DEC1 promoter, and between -863 and -258 in the DEC2 promoter, were responsible for the hypoxia- or hypoxia-inducible factor-1alpha (HIF-1alpha)-induced transcription. In these regions, we identified functional hypoxia response elements (HREs) that bound to HIF-1alpha and HIF-1beta. In addition to an HIF-1 binding site consensus sequence, the DEC1 HRE had cAMP response element-like and CACAG sequences, which were also involved in the transcription activation in response to HIF-1alpha. Although the DEC2 HRE did not have a cAMP response element-like or CACAG sequence, it showed a higher affinity for HIF-1 than did the DEC1 HRE. Because DEC1 and DEC2 are directly inducible by HIF-1, these transcription factors may be crucial for the adaptation to hypoxia.