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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.

Styrktaraðili: 
  • Styrktaraðili er á ensku 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.
Birtist í: 
  • Nature Cell Biology, 2012, 14, 201-208
ISSN: 
  • 1465-7392
Samþykkt: 
  • 13.7.2015
URI: 
  • http://hdl.handle.net/1946/22346


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