Sun and survival with Hif1α

The degranulation two-step egranulation of mast cells involves a two-step process, report Nishida et al. on page 115. First, antigen stimulation triggers microtubule polymerization and granule translocation to the cell surface in a calcium-independent process. Second, the granules fuse with the plasma membrane in a well-characterized calcium-dependent process. Mast cells are so full of granules that degranulation was thought to occur through granule-to-membrane fusion and granule-to-granule fusion, without the need for granule transport. However, inhibition of microtubule polymerization blocked degranulation. In response to antigen stimulation, Nishida et al. found that tubulin staining increased and fluorescently tagged granules translocated to the cell surface before exocytosis. Removal of calcium from the culture medium prevented granule fusion to the membrane but had no effect on microtubule polymerization or granule movement, suggesting that the steps are distinct. When the team stimulated mast cells deficient for Fyn or Lyn tyrosine kinase signaling proteins, the cells had reduced degranulation, as previously reported. However, only the D Sun and survival with Hif1 tabilized Hif1 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 Hif1 . This should help cells survive the sun’s insults, but may also aid in melanoma development. Oxygen-dependent Hif1 regulation occurs primarily at the posttranslational level. But Busca et al. report that cAMP acts as an independent stimulant of Hif1 expression by increasing transcription of the Hif1a gene (which encodes Hif1 ) 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 Hif1 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 Hif1 was present. Although cAMP-MITF activation of Hif1 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 Hif1 ’s pro-survival role in tumor cells. S Regulating the prostate rostate cancer and benign prostatic hyperplasia result from excessive proliferation of cells in this organ, likely due to deregulation of stem cells. Salm et al. (page 81) find that cells in the proximal region of the prostate, where the stem cells reside, respond differently to TGFrelative to distal cells in mice. A regulatory teeter-totter between TGFexpression, which inhibits cell proliferation and pro-growth P