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1 Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA; Graduate program in Genetics, Michigan State University, East Lansing, MI, USA
2 Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA
3 Genomics Institute of the Novartis Research Foundation, San Diego, CA, USA
4 Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA; National Food Safety and Toxicology Center, Michigan State University, East Lansing, MI, USA; Center for Integrative Toxicology, Michigan State University, East Lansing, MI, USA
* To whom correspondence should be addressed. E-mail: lapres{at}msu.edu.
Cellular, local, and organismal responses to low oxygen availability occur during processes such as anaerobic metabolism, and wound healing; and pathological conditions such as stroke and cancer. These responses include increases in glycolytic activity, vascularization, breathing and red blood cell production. These responses are mediated in part by the hypoxia inducible factors (HIFs), which receive information on O2 levels from a group of iron and oxygen-dependent hydroxylases. Hypoxia mimics, such as cobalt chloride, nickel chloride, and deferoxamine act to simulate hypoxia by altering the iron status of these hydroxylases. To determine if these mimics are appropriate substitutes for lower oxygen tension evoked naturally, we compared transcriptional responses of a Hep3B cell line using high-density oligonucleotide arrays. A battery of core genes was identified that was shared by all four treatments (hypoxia, cobalt, nickel and deferoxamine) including glycolytic enzymes, cell cycle regulators and apoptotic genes. Importantly, cobalt, nickel and deferoxamine influenced transcription of distinct sets of genes that were not affected by cellular hypoxia. These global responses to hypoxia indicate a balancing act between adaptation and programmed cell death, and suggest caution in the use of hypoxia mimics as a substitute for low O2 tension that occurs in vivo.
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