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Repression of -Fetoprotein Gene Expression under Hypoxic Conditions in Human Hepatoma Cells

Characterization of a Negative Hypoxia Response Element That Mediates Opposite Effects of Hypoxia Inducible Factor-1 and c-Myc¹

Centre de Recherche sur l’Endocrinologie Moléculaire et le Développement, CNRS-UPR 9078, 92190 Meudon-Bellevue [N. M. M., C. C., B. B-J., H. N-C., J-L. D.], and Laboratoire de Biochimie C, Hôpital de la Pitié, 75013 Paris [M-A. B.], France

Hypoxia is an important component of many pathological processes including cancerogenesis and cirrhosis. We have attempted to identify additional hepatic genes sensitive to hypoxia by postulating that genes with possible binding sites for hypoxia inducible factor-1 (HIF-1) are regulated by hypoxia. A computer analysis identified the oncodevelopmental -fetoprotein gene (afp) as one of them. The amounts of both -fetoprotein mRNA and protein were decreased under hypoxic conditions in HepG2 hepatoma cells. Stability of afp mRNA was not altered, and de novo synthesis of proteins was required. Transfection experiments in HepG2 cells showed that both hypoxia and overproduction of HIF-1 specifically repressed the transcriptional activity of the rat afp regulatory region through the sequence 5'-CACGTGGG-3' located at -3625 to -3619. Mutation in this sequence strongly impaired these repressions. Interestingly, this sequence was a functional stimulatory target for c-Myc, suggesting that c-Myc regulates afp gene expression. Lastly, the amounts of c-myc mRNA and protein were reduced when these cells were grown under hypoxic conditions. Taken together, these results suggest the existence of a possible competition between HIF-1 and c-Myc that could modulate the transcriptional activity of the afp gene in response to hypoxia.

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