HIF-1:: master and commander of the hypoxic world -: A pharmacological approach to its regulation by siRNAs

The hypoxia-inducible factor-1 (HIF-1) is primarily involved in the sensing and adapting of cells to changes in the O(2) level, which is essential for their viability. It is important that this critical transcription factor be tightly regulated in order for cells to respond to a wide range of O(2) concentrations. HIF-1 regulation by post-translational modification is the central theme of the scenario of O(2) homeostasis. The alpha subunit of HIF-1 is the principal actor while the supporting actors (PHDs, FIH-1, ARD1, CITED2, p300...) all contribute to the complexity of the grand finale. It is well established that HIF-1 expression and activation correlates with tumor progression and resistance to cancer treatments. We will introduce the different actors involved in HIF-1 regulation, and their mechanisms of action via invalidation by siRNAs and discuss therapies targeting HIF-1, to selectively kill tumor cells that adapt to low O(2) concentrations. (C) 2004 Elsevier Inc. All rights reserved.