All mammalian cells release small endosome-derived exosomes that function in intercellular communication, but the secretion process is poorly understood. Verweij et al. developed a live-imaging approach and demonstrate that external cues can trigger exosome release from a subpopulation of multivesicular bodies by phosphorylating the target membrane SNARE SNAP23 at serine residue 110.

Hypoxia induces transcription of a range of physiologically important genes including erythropoietin and vascular endothelial growth factor. The transcriptional activation is mediated by the hypoxia-inducible factor-1 (HIF-1), a heterodimeric member of the basic helix ± loop ± helix PAS family, composed of a and b subunits. HIF-1a shares 48 per cent identity with the recently identi®ed HIF-2a protein that is also stimulated by hypoxia. In a previous study of hemangioblastomas, the most frequent manifestation of hereditary von HippelLindau disease (VHL), we found elevated levels of vascular endothelial growth factor and HIF-2a mRNA in stromal cells of the tumors. Mutations of the VHL tumor suppressor gene are associated with a variety of tumors such as renal clear cell carcinomas (RCC). In this study, we analysed the expression of the hypoxiainducible factors HIF-1a and HIF-2a in a range of VHL wildtype and VHL de®cient RCC cell lines. In the presence of functional VHL protein, HIF-1a mRNA levels are elevated, whereas HIF-2a mRNA expression is increased only in cells lacking a functional VHL gene product. On the protein levels, however, in VHL de®cient cell lines, both HIF-a subunits are constitutively expressed, whereas re-introduction of a functional VHL gene restores the instability of HIF-1a and HIF-2a proteins under normoxic conditions. Moreover, immunohistochemical analyses of RCCs and hemangioblastomas demonstrate up-regulation of HIF-1a and HIF-2a in the tumor cells. The data presented here provide evidence for a role of the VHL protein in regulation of angiogenesis and erythropoiesis mediated by the HIF-1a and HIF-2a proteins. Oncogene (2000) 19, 5435 ± 5443.

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