The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity

School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre, NG7 2UH, UK.
Nature Cell Biology (Impact Factor: 19.68). 02/2012; 14(2):201-8. DOI: 10.1038/ncb2424
Source: PubMed


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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    • "to hypoxia (Foxler et al., 2012), hippo signaling (Das Thakur et al., 2010), PIP2 signaling (Kisseleva et al., 2005) and stress fiber maintenance (Smith et al., 2010; Hoffman et al., 2012). Molecular genetic analysis in mouse suggests that vertebrate zyxin family members assume functionally redundant cellular roles, since mouse knockouts of LPP and zyxin exhibit few overt phenotypic abnormalities (Hoffman et al., 2003; Vervenne et al., 2009), whereas Drosophila mutants are inviable (Das Thakur et al., 2010; Renfranz et al., 2010). "
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    Development 09/2014; 141(20). DOI:10.1242/dev.108217 · 6.46 Impact Factor
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    • "Under normal oxygen levels, HIF-1α is unstable because PHDs use molecular oxygen as a substrate to hydroxylate proline residues of HIF-1α. The hydroxylated HIF-1α is recognized by the von Hippel-Lindau tumor suppressor (VHL), and targeted for proteasomal degradation [24,26,32]. It has been demonstrated that CoCl2 is an effective inducer of chemical hypoxia by inhibiting the activity of PHDs and preventing degradation of HIF-1α protein [25,33]. "
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    PLoS ONE 12/2013; 8(12):e82827. DOI:10.1371/journal.pone.0082827 · 3.23 Impact Factor
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    • "The up-regulation of this TF in the preeclamptic placenta seems coherent with the detection of an over-representation of TFBS for E2F1 among the down-regulated genes. On the other hand, LIMD1 has been recently involved in the regulation of the hypoxia response through a mechanism involving HIF1-α degradation [83]. LIMD1 up-regulation in the preeclamptic placenta might result from a feed-back mechanism aiming to regulate the transcriptional activity of the HIF complex. "
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