1. ¹Department of Neurosurgery, University of Utah, Salt Lake City, UT 84132, USA
2. ²Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84132, USA

Correspondence: LE Huang, Department of Neurosurgery, University of Utah, Building 550, 5th Floor, 175 North Medical Drive East, Salt Lake City, Utah 84132, USA. Tel: 801 585 3221; Fax: 801 585 7492; E-mail: eric.huang@hsc.utah.edu

Received 4 October 2007; Revised 21 November 2007; Accepted 22 November 2007; Published online 11 January 2008.

Abstract

The past decade of research on hypoxic responses has provided a considerable understanding of how cells respond to hypoxic stress at the molecular level, thanks to the identification and molecular cloning of the hypoxia-inducible transcription factor, HIF-1. Numerous target genes have since been identified to account for various aspects of the hypoxic response, including angiogenesis and glycolysis. Yet, fundamental questions remain regarding the mechanisms by which hypoxia controls cell proliferation, genetic instability, mitochondrial biogenesis, and oxidative respiration in cancer cells. Although the proto-oncoprotein c-Myc appears to be the diametrical opposite of HIF-1 in most of these processes, recent studies indicate that c-Myc is an integral part of the HIF-–c-Myc molecular pathway in the hypoxic response. It has been shown that HIF- engages with Myc by various mechanisms to achieve oxygen homeostasis for cell survival. This article focuses on the intricate roles of c-Myc in the hypoxic response, discusses various mechanisms controlling c-Myc activity by HIF- for the regulation of hypoxia-responsive genes, and emphasizing the outcome of gene expression apparently dependent upon hypoxic conditions, cellular context, and gene promoter.