Characterization of different isoforms of the HIF prolyl hydroxylase PHD1 generated by alternative initiation
Open Access
- 14 June 2006
- journal article
- Published by Portland Press Ltd. in Biochemical Journal
- Vol. 397 (1), 179-186
- https://doi.org/10.1042/bj20051996
Abstract
The heterodimeric transcription factor HIF (hypoxia-inducible factor) is central to the regulation of gene expression by oxygen. Three oxygen-dependent prolyl hydroxylase enzymes [PHD1 (prolyl hydroxylase domain 1), PHD2 and PHD3] control the abundance of HIF. In the presence of oxygen, they hydroxylate specific proline residues in HIF-α, allowing recognition by pVHL (von Hippel-Lindau protein) and subsequent ubiquitylation and proteasomal destruction. The precise roles and regulation of these enzymes are therefore of particular importance in understanding the physiological and pathological responses to hypoxia. In the present study, we define the existence of two species of PHD1 and provide evidence that they are generated by alternative translational initiation. We demonstrate that these alternative forms are both biologically active with similar HIF prolyl hydroxylase activity but that they differ in their responses to oestrogen, cell confluence and proteasomal inhibition. We show that the two PHD1 species are subject to proteolytic regulation but differ markedly in their protein stability. Though each isoform has the potential to interact with members of the Siah (seven in absentia homologue) ubiquitin ligase family, genetic studies indicated that other proteolytic mechanisms are responsible for control of stability under the conditions examined. The data define the existence of a further level of control in the pathway that regulates cellular responses to hypoxia.This publication has 25 references indexed in Scilit:
- Regulation of the prolyl hydroxylase domain protein 2 (phd2/egln-1) gene: identification of a functional hypoxia-responsive elementBiochemical Journal, 2005
- Determination and comparison of specific activity of the HIF‐prolyl hydroxylasesFEBS Letters, 2004
- Differential Function of the Prolyl Hydroxylases PHD1, PHD2, and PHD3 in the Regulation of Hypoxia-inducible FactorJournal of Biological Chemistry, 2004
- Siah2 Regulates Stability of Prolyl-Hydroxylases, Controls HIF1α Abundance, and Modulates Physiological Responses to HypoxiaCell, 2004
- The von Hippel Lindau/Hypoxia-inducible Factor (HIF) Pathway Regulates the Transcription of the HIF-Proline Hydroxylase Genes in Response to Low OxygenOnline Journal of Public Health Informatics, 2003
- Hypoxia Up-regulates Prolyl Hydroxylase ActivityOnline Journal of Public Health Informatics, 2003
- Characterization of the Human Prolyl 4-Hydroxylases That Modify the Hypoxia-inducible FactorJournal of Biological Chemistry, 2003
- Differential regulation of HIF-1α prolyl-4-hydroxylase genes by hypoxia in human cardiovascular cellsBiochemical and Biophysical Research Communications, 2003
- Mapping, Characterization, and Expression Analysis of the SM-20 Human Homologue, C1orf12, and Identification of a Novel Related Gene, SCAND2Genomics, 2000
- Purification and Characterization of Hypoxia-inducible Factor 1Journal of Biological Chemistry, 1995