Arrest-defective-1 Protein, an Acetyltransferase, Does Not Alter Stability of Hypoxia-inducible Factor (HIF)-1α and Is Not Induced by Hypoxia or HIF*

Rebecca Bilton, Nathalie Mazure, Eric Trottier, Maurice Hattab, Marc-André Déry, Darren E. Richard, Jacques Pouysségur, M. Christiane Brahimi-Horn

Research output: Contribution to journalArticlepeer-review

92 Citations (Scopus)

Abstract

The hypoxia-inducible factor (HIF) is a key player in a transcriptional pathway that controls the hypoxic response of mammalian cells. Post-translational modification of the α subunit of HIF determines its half-life and activity. Among the multiple reported modifications, acetylation, by an acetyltransferase termed arrest-defective-1 protein (AMD1), has been reported to decrease HIF-1α stability and therefore impact on hypoxic gene expression. In contrast, we report that both overexpression and silencing of ARD1 had no impact on the stability of HIF-1α or -2α and that cells silenced for ARD1 maintained hypoxic nuclear localization of HIF-1α. In addition, we show that the ARD1 mRNA and protein levels are not regulated by hypoxia in several human tumor cell lines, including cervical adenocarcinoma HeLa cells, fibrosarcoma HT1080 cells, adenovirus-transformed human kidney HEK293 cells, and human breast cancer MCF-7 cells. Using two model systems ((a) wild-type and HIF-1α-null mouse embryo fibroblasts and (b) HeLa cells silenced for HIF-1α or -2α by RNA interference), we demonstrate that the level of expression of the ARD1 protein is independent of HIF-1α and -2α. We also demonstrate that ARD1 is a stable, predominantly cytoplasmic protein expressed in a broad range of tissues, tumor cell lines, and endothelial cells. Taken together, our findings demonstrate that ARD1 has limited, if any, impact on the HIF signaling pathway.

Original languageEnglish
Pages (from-to)31132-31140
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number35
DOIs
Publication statusPublished - 2 Sep 2005
Externally publishedYes

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