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Vinsamlegast notið þetta auðkenni þegar þið vitnið til verksins eða tengið í það: http://hdl.handle.net/1946/22346

Titill: 
  • Titill er á ensku The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity
Útgáfa: 
  • Janúar 2012
Útdráttur: 
  • Útdráttur er á ensku

    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.

Birtist í: 
  • Nature Cell Biology, 2012, 14, 201-208
ISSN: 
  • 1465-7392
Tengd vefslóð: 
  • http://www.nature.com/ncb/journal/v14/n2/pdf/ncb2424.pdf
  • http://web.b.ebscohost.com/ehost/pdfviewer/pdfviewer?sid=01feef01-26a6-46c7-8f98-f73d26aa9d9b%40sessionmgr198&vid=1&hid=118
  • http://search.proquest.com/docview/1038915410
  • http://www.ncbi.nlm.nih.gov/pubmed/22286099
  • http://www.readcube.com/articles/10.1038%2Fncb2424
  • http://www.pubfacts.com/detail/22286099/The-LIMD1-protein-bridges-an-association-between-the-prolyl-hydroxylases-and-VHL-to-repress-HIF-1-ac
  • https://www.researchgate.net/publication/221785676_The_LIMD1_protein_bridges_an_association_between_the_prolyl_hydroxylases_and_VHL_to_repress_HIF-1_activity
Samþykkt: 
  • 13.7.2015
URI: 
  • http://hdl.handle.net/1946/22346


Skrár
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Foxler2012NatureCellBiol.pdf10.89 MBOpinnHeildartextiPDFSkoða/Opna