dc.contributor |
Háskóli Íslands |
dc.contributor |
University of Iceland |
dc.contributor.author |
Foxler, Daniel E. |
dc.contributor.author |
Bridge, Katherine S. |
dc.contributor.author |
James, Victoria |
dc.contributor.author |
Webb, Thomas M. |
dc.contributor.author |
Mee, Maureen |
dc.contributor.author |
Wong, Sybil C. K. |
dc.contributor.author |
Feng, Yunfeng |
dc.contributor.author |
Constantin-Teodosiu, Dumitru |
dc.contributor.author |
Petursdottir, Thorgunnur Eyfjord |
dc.contributor.author |
Bjornsson, Johannes |
dc.contributor.author |
Ingvarsson, Sigurður |
dc.contributor.author |
Ratcliffe, Peter J. |
dc.contributor.author |
Longmore, Gregory D. |
dc.contributor.author |
Sharp, Tyson V. |
dc.date.accessioned |
2019-11-19T08:52:20Z |
dc.date.available |
2019-11-19T08:52:20Z |
dc.date.issued |
2012-01-29 |
dc.identifier.citation |
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 |
dc.identifier.issn |
1465-7392 |
dc.identifier.issn |
1476-4679 (eISSN) |
dc.identifier.uri |
https://hdl.handle.net/20.500.11815/1344 |
dc.description |
Publisher's version (útgefin grein) |
dc.description.abstract |
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. |
dc.description.sponsorship |
K.S.B. is supported by a Biotechnology and Biological Sciences Research Council Doctorate Training Award. V.J. and D.E.F. were supported by funding from the Biotechnology and Biological Sciences Research Council (BB/F006470/1 and BB/I007571/1) awarded to T.V.S. |
dc.format.extent |
201-208 |
dc.language.iso |
en |
dc.publisher |
Springer Nature |
dc.relation.ispartofseries |
Nature Cell Biology;14(2) |
dc.rights |
info:eu-repo/semantics/openAccess |
dc.subject |
Cell Biology |
dc.subject |
LIMD1 |
dc.subject |
VHL |
dc.subject |
HIF |
dc.subject |
Transcription factor |
dc.subject |
Protein degradation |
dc.subject |
Tumour suppressor |
dc.subject |
Hypoxia regulation |
dc.subject |
Frumulíffræði |
dc.subject |
Prótín |
dc.title |
The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity |
dc.type |
info:eu-repo/semantics/article |
dc.description.version |
Peer Reviewed |
dc.identifier.journal |
Nature Cell Biology |
dc.identifier.doi |
10.1038/ncb2424 |
dc.contributor.department |
Institute for Experimental Pathology, Keldur (UI) |
dc.contributor.department |
Tilraunastöð í meinafræði að Keldum (HÍ) |