Increased activity of hypoxia-inducible factor 1 is associated with early embryonic lethality in Commd1 null mice

doi:10.1128/MCB.01932-06

Increased activity of hypoxia-inducible factor 1 is associated with early embryonic lethality in Commd1 null mice

2023-03-27

110

OA

AI

DOI：10.1128/MCB.01932-06

Original

Save

View PDF

Abstract

En 中文

OMMD1 (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-KB 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 postcoiturn. (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 alpha stability. Consistent with these observations, COMMD1 physically associates with HIF-1 alpha and inhibits HIF-1 alpha 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.

Keywords:

COPPER TOXICOSIS

KAPPA-B

BEDLINGTON TERRIER

O-2 HOMEOSTASIS

GENE-EXPRESSION

FACTOR 1-ALPHA

MOUSE MURR1

PROTEIN

IDENTIFICATION

ACTIVATION

Increased activity of hypoxia-inducible factor 1 is associated with early embryonic lethality in Commd1 null mice

Abstract

AI Summary

Journal

Organization