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Molecular and Cellular Biology, June 2007, p. 4142-4156, Vol. 27, No. 11
0270-7306/07/$08.00+0     doi:10.1128/MCB.01932-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Increased Activity of Hypoxia-Inducible Factor 1 Is Associated with Early Embryonic Lethality in Commd1 Null Mice

Complex Genetics Section, DBG-Department of Medical Genetics, University Medical Center Utrecht, 3584 CG Utrecht,¹ Laboratory for Metabolic and Endocrine Diseases, University Medical Center Utrecht, 3584 EA Utrecht,² Department of Pathology, University Medical Center Utrecht, 3508 GA Utrecht,⁴ Department of Genetics, University Medical Center Groningen, 9700 RB Groningen, The Netherlands,⁶ Genetic Disease Research Branch,³ Oncogenesis and Development Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892⁵

Received 12 October 2006/ Returned for modification 15 November 2006/ Accepted 11 March 2007

COMMD1 (previously known as MURR1) belongs to a novel family of proteins termed the copper metabolism gene MURR1 domain (COMMD) family. The 10 COMMD family members are well conserved between vertebrates, but the functions of most of the COMMD proteins are unknown. We recently established that COMMD1 is associated with the hepatic copper overload disorder copper toxicosis in Bedlington terriers. Recent in vitro studies indicate that COMMD1 has multiple functions, including sodium transport and NF-B signaling. To elucidate the function of Commd1 in vivo, we generated homozygous Commd1 null (Commd1^–/–) mice. Commd1^–/– embryos died in utero between 9.5 and 10.5 days postcoitum (dpc), their development was generally retarded, and placenta vascularization was absent. Microarray analysis identified transcriptional upregulation of hypoxia-inducible factor 1 (HIF-1) target genes in 9.5-dpc Commd1^–/– embryos compared to normal embryos, a feature that was associated with increased Hif-1 stability. Consistent with these observations, COMMD1 physically associates with HIF-1 and inhibits HIF-1 stability and HIF-1 transactivation in vitro. Thus, this study identifies COMMD1 as a novel regulator of HIF-1 activity and shows that Commd1 deficiency in mice leads to embryonic lethality associated with dysregulated placenta vascularization.

Published ahead of print on 19 March 2007.

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