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- _4 value "Experiments on cells bearing inactivating mutations in the HIF pathway have emphasized the importance of HIF (particularly HIF-1alpha) on the regulation of genes involved in angiogenesis64, 68, 69, 70. For a substantial number of these genes, promoter analysis has also clearly identified HREs that interact directly with HIF. The expression of other genes may be affected indirectly by secondary cascades of gene regulation. Even with respect to a single molecule, there may be many interfaces with hypoxia and hypoxia pathways (Fig. 3). This is well-illustrated for VEGF. In hypoxia, VEGF transcription is upregulated by HIF18, 19, mRNA stability is increased by binding of proteins to specific sequences in the 3' UTR71, and an internal ribosomal entry site allows preserved translation in the face of normal cellular hypoxic shutdown72. The biological activity of secreted VEGF is further influenced by hypoxia-inducible expression of the Flt-1 receptor49, post-transcriptional regulation of the Kdr receptor50 and VEGF-induced effects on soluble Flt-1 (ref. 73), which inhibits VEGF action (Fig. 3). Essential role of HIF in developmental angiogenesis In keeping with the central role of HIF in responses to hypoxia observed in tissue culture, targeted inactivation of either Hif1a (refs. 68,70,74) or Arnt (encoding HIF-1beta)75 in the mouse results in abnormal vascular development and embryonic lethality." provenance.
- _4 wasQuotedFrom 12778166 provenance.