Hypoxia-inducible factor-1alpha (HIF-1α) plays crucial roles in tumor promotion by transactivating approximately 60 kinds of its target genes. Recently, we reported a novel splice variant HIF-1α 785, which is regulated primarily by phorbol ester. This variant can be stabilized under normoxic conditions because it loses an acetylation site Lys532. Its expression was found to promote xenografted tumor growth in nude mice. We here found that the Ras oncogene regulates HIF-1α 785 expression via the Raf/MEK/ERK pathway, and that both phorbol ester and epidermal growth factor also induced HIF-1α 785 via the same pathway. We also identified the nonhypoxic regulatory domain responsible for phorbol ester-induced HIF-1α 785 expression. These results imply that HIF-1α 785 may play an important role in tumor promotion mediated by the Ras oncogene, phorbol ester or tumor growth factors.