Titill: | The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity |
Höfundur: |
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Útgáfa: | 2012-01-29 |
Tungumál: | Enska |
Umfang: | 201-208 |
Háskóli/Stofnun: | Háskóli Íslands University of Iceland |
Deild: | Institute for Experimental Pathology, Keldur (UI) Tilraunastöð í meinafræði að Keldum (HÍ) |
Birtist í: | Nature Cell Biology;14(2) |
ISSN: | 1465-7392 1476-4679 (eISSN) |
DOI: | 10.1038/ncb2424 |
Efnisorð: | Cell Biology; LIMD1; VHL; HIF; Transcription factor; Protein degradation; Tumour suppressor; Hypoxia regulation; Frumulíffræði; Prótín |
URI: | https://hdl.handle.net/20.500.11815/1344 |
Tilvitnun:Foxler, D. E., Bridge, K. S., James, V., Webb, T. M., Mee, M., Wong, S. C. K., . . . Sharp, T. V. (2012). The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity. Nature Cell Biology, 14(2), 201-208. doi:10.1038/ncb2424
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Útdráttur: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.
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Athugasemdir:Publisher's version (útgefin grein)
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