Stabilized Hif1α helps cells to survive in the face of low oxygen. Now, Busca et al. (page 49) report that elevated cAMP, which occurs in melanocytes downstream of UV irradiation from the sun, also leads to higher Hif1α. This should help cells survive the sun's insults, but may also aid in melanoma development.
Oxygen-dependent Hif1α regulation occurs primarily at the posttranslational level. But Busca et al. report that cAMP acts as an independent stimulant of Hif1α expression by increasing transcription of the Hif1a gene (which encodes Hif1α) in melanocytes.
The elevated cAMP up-regulates expression of MITF, a key melanocyte-specific transcription factor. When the team performed a series of reporter gene experiments using MITF and Hif1a constructs, they saw that MITF was necessary and sufficient to turn on Hif1α expression. Furthermore, MITF bound directly to Hif1a promoter DNA, based on ChIP analysis. Significantly, cells that had elevated cAMP were resistant to cell death triggers, but only when Hif1α was present.
Although cAMP-MITF activation of Hif1α was not detected in other cell types—presumably due to the absence of MITF—the scientists think similar transcriptional regulation of the Hif1a gene likely occurs elsewhere. If that is true, researchers may have one more tool to turn off Hif1α's pro-survival role in tumor cells.