دورية أكاديمية
The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity.
| العنوان: | The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity. |
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| المؤلفون: | Foxler, Daniel E, Bridge, Katherine S, James, Victoria, Webb, Thomas M, Mee, Maureen, Wong, Sybil C K, Feng, Yunfeng, Constantin-Teodosiu, Dumitru, Petursdottir, Thorgunnur Eyfjord, Bjornsson, Johannes, Ingvarsson, Sigurdur, Ratcliffe, Peter J, Longmore, Gregory D, Sharp, Tyson V |
| المساهمون: | School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre, NG7 2UH, UK. |
| سنة النشر: | 2012 |
| المجموعة: | Hirsla - Landspítali University Hospital research archive |
| مصطلحات موضوعية: | Cell Hypoxia, Cell Line, Tumor, HEK293 Cells, HeLa Cells, Humans, Hydroxylation, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoblotting, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, LIM Domain Proteins, Models, Biological, Polyubiquitin, Procollagen-Proline Dioxygenase, Proteasome Endopeptidase Complex, Protein Binding, RNA Interference, Transfection, Two-Hybrid System Techniques, Ubiquitination, Von Hippel-Lindau Tumor Suppressor Protein |
| الوصف: | There are three prolyl hydroxylases (PHD1, 2 and 3) that regulate the hypoxia-inducible factors (HIFs), the master transcriptional regulators that respond to changes in intracellular O(2) tension. In high O(2) tension (normoxia) the PHDs hydroxylate two conserved proline residues on HIF-1α, which leads to binding of the von Hippel-Lindau (VHL) tumour suppressor, the recognition component of a ubiquitin-ligase complex, initiating HIF-1α ubiquitylation and degradation. However, it is not known whether PHDs and VHL act separately to exert their enzymatic activities on HIF-1α or as a multiprotein complex. Here we show that the tumour suppressor protein LIMD1 (LIM domain-containing protein) acts as a molecular scaffold, simultaneously binding the PHDs and VHL, thereby assembling a PHD-LIMD1-VHL protein complex and creating an enzymatic niche that enables efficient degradation of HIF-1α. Depletion of endogenous LIMD1 increases HIF-1α levels and transcriptional activity in both normoxia and hypoxia. Conversely, LIMD1 expression downregulates HIF-1 transcriptional activity in a manner depending on PHD and 26S proteasome activities. LIMD1 family member proteins Ajuba and WTIP also bind to VHL and PHDs 1 and 3, indicating that these LIM domain-containing proteins represent a previously unrecognized group of hypoxic regulators. ; Biotechnology and Biological Sciences Research Council BB/F006470/1 BB/I007571/1 |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1476-4679 |
| العلاقة: | http://www.nature.com/ncb/journal/v14/n2/full/ncb2424.htmlTest; http://dx.doi.org/10.1038/ncb2424Test; Nat. Cell Biol. 2012, 14(2):201-8; http://hdl.handle.net/2336/298913Test; Nature cell biology |
| DOI: | 10.1038/ncb2424 |
| الإتاحة: | https://doi.org/10.1038/ncb2424Test http://hdl.handle.net/2336/298913Test |
| حقوق: | Archived with thanks to Nature cell biology ; Landspitali Access - LSH-aðgangur |
| رقم الانضمام: | edsbas.87D9B9C2 |
| قاعدة البيانات: | BASE |
| تدمد: | 14764679 |
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| DOI: | 10.1038/ncb2424 |