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

Foxler, Daniel E.; Bridge, Katherine S.; James, Victoria; Webb, Thomas M.; Mee, Maureen; Wong, Sybil C K; Feng, Yunfeng; Constantin‐Teodosiu, Dumitru; Petursdottir, Thorgunnur Eyfjord; Björnsson, Jóhannes; Ingvarsson, Sigurður; Ratcliffe, Peter J.; Longmore, Gregory D.; Sharp, Tyson V.

doi:10.1038/ncb2424

Cited by 86 publications

(85 citation statements)

References 39 publications

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“…Our results indicate that a single LIM domain of FHL1 is sufficient for interaction with HIF1a. Recently, the tumor suppressor protein LIMD1 (LIM domaincontaining protein 1) has been shown to bind prolyl hydroxylases (PHDs), the enzymes involved in regulation of HIF1 hydroxylation, and the VHL tumor suppressor, the recognition component of a ubiquitin-ligase complex (29). Such interaction creates an enzymatic niche that enables efficient degradation of HIF1.…”

Section: Discussionmentioning

confidence: 99%

FHL family members suppress vascular endothelial growth factor expression through blockade of dimerization of HIF1α and HIF1β

et al. 2012

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SummaryFour and a half LIM domain (FHL) proteins belong to a family of LIM-only proteins that have been implicated in the development and progression of various types of cancers. However, the role of FHL proteins in tumor angiogenesis remains to be elucidated. Herein, we demonstrate that FHL1-3 decrease the promoter activity and expression of vascular endothelial growth factor (VEGF), the key regulator of angiogenesis in cancer growth and progression as well as an important target gene of the transcription factor hypoxia-inducible factor 1 (HIF1a/ HIF1b). FHL1-3 interacted with HIF1a both in vitro and in vivo. A single LIM domain of FHL1 was sufficient for its interaction with HIF1a. FHL1 interacted with the HIF1a region containing basic helix-loop-helix (bHLH) motif and PER-ARNT-SIM domain, both of which aid in dimerization with HIF1b and DNA binding. FHL1-3 inhibited HIF1 transcriptional activity and HIF1-mediated VEGF expression in a hypoxia-independent manner. Moreover, FHL1 blocked HIF1a-HIF1b heterodimerization and HIF1a recruitment to the VEGF promoter. These data suggest that FHL proteins are involved in negative regulation of VEGF possibly by interfering with the dimerization and DNA binding of HIF1 subunits and may play an important role in tumor angiogenesis. Keywords four and a half LIM domain; vascular endothelial growth factor; hypoxia-inducible factor 1; protein-protein interaction; transcriptional activity.

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Section: Discussionmentioning

confidence: 99%

FHL family members suppress vascular endothelial growth factor expression through blockade of dimerization of HIF1α and HIF1β

et al. 2012

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“…Notably, some HIF3A isoforms contain only a single prolyl hydroxylation site, while others are missing this region entirely and are therefore not subject to regulation in response to oxygen. Proline hydroxylation allows binding of the von Hippel Lindau (VHL) E3 ubiquitin ligase complex, which poly-ubiquitinates the alpha subunits triggering their degradation by the proteasome (Huang et al, 1998, Ohh et al, 2000, Tanimoto et al, 2000, Foxler et al, 2012). It is worth mentioning that PHD2 and PHD3 (EGLN3) are HIF target genes, which sets up possibly negative feedback loops within the network.…”

Section: The Hif Family Of Transcription Factorsmentioning

confidence: 99%

Transcriptional regulation by hypoxia inducible factors

Dengler¹,

Galbraith²,

Espinosa³

2013

Critical Reviews in Biochemistry and Molecular Biology

640

540

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The cellular response to oxygen deprivation is governed largely by a family of transcription factors known as Hypoxia Inducible Factors (HIFs). This review focuses on the molecular mechanisms by which HIFs regulate the transcriptional apparatus to enable the cellular and organismal response to hypoxia. We discuss here how the various HIF polypeptides, their post-translational modifications, binding partners and transcriptional cofactors affect RNA polymerase II activity to drive context-dependent transcriptional programs during hypoxia.

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“…SENP3 is responsible for the enhancement of HIF-1 transactivation under mild oxidative stress via de-sumoylation [31]. The LIMD1 protein bridges an association between the PHDs and VHL to inhibit HIF-1 activity [32].…”

Section: Hif and The Regulation Of The Hypoxia Signaling Pathwaymentioning

confidence: 99%

The hypoxia signaling pathway and hypoxic adaptation in fishes

Xiao

2015

Sci. China Life Sci.

140

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The hypoxia signaling pathway is an evolutionarily conserved cellular signaling pathway present in animals ranging from Caenorhabditis elegans to mammals. The pathway is crucial for oxygen homeostasis maintenance. Hypoxia-inducible factors (HIF-1α and HIF-2α) are master regulators in the hypoxia signaling pathway. Oxygen concentrations vary a lot in the aquatic environment. To deal with this, fishes have adapted and developed varying strategies for living in hypoxic conditions. Investigations into the strategies and mechanisms of hypoxia adaptation in fishes will allow us to understand fish speciation and breed hypoxia-tolerant fish species/strains. This review summarizes the process of the hypoxia signaling pathway and its regulation, as well as the mechanism of hypoxia adaptation in fishes. Approximately 2.5 billion years ago, photosynthesis led to the accumulation of oxygen to levels that were likely toxic to many obligate anaerobes. However, increased availability of atmospheric O 2 led to the evolution of an extraordinarily efficient system of oxidative phosphorylation. In this system, chemical energy stored in the carbon bonds of organic molecules is transferred to the high-energy phosphate bond in ATP, which is then used to power physicochemical reactions in living cells [1]. Additionally, O 2 serves as the final electron acceptor in oxidative phosphorylation, which is not only required for energy production, but is also the direct substrate of many enzymes. Thus, it is critical for the growth, development, and reproduction of organisms. Consequently, metazoans have evolved complicated systems of cellular metabolism and physiology to maintain oxygen homeostasis and have developed a biochemical response to low oxygen levels [2]. There are a number of oxygen-sensing pathways that promote hypoxia tolerance by activating transcription and inhibiting translation: the energy and nutrient sensor mTOR, the unfolded protein response that activates the endoplasmic stress response, and the nuclear factor (NF)-B transcriptional response [3]. However, hypoxia-inducible factors (HIFs) are recognized as master regulators of the cellular response to hypoxic stress [4,5]. The hypoxia signaling pathway is evolutionarily conserved from Caenorhabditis elegans to human beings and it activates similar or homogenous gene expression, resulting in similar physical and biochemical responses. Compared with the terrestrial environment, oxygen concentrations vary greatly in the aquatic environment [6]. Thus, compared with most birds and mammals, fishes are tolerant of this varying oxygen availability. Natural selection by oxygen concentration has facilitated the evolution of fishes with a range of adaptations to variable oxygen concentration. Even in waters at the same latitude, closely related species or different strains within a species exhibit varied adaptations to oxygen concentration. Additionally, closely related fishes distributed in waters at different latitudes exhibit extensive variation in their tolerance of hypoxia. De...

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

Cited by 86 publications

References 39 publications

FHL family members suppress vascular endothelial growth factor expression through blockade of dimerization of HIF1α and HIF1β

FHL family members suppress vascular endothelial growth factor expression through blockade of dimerization of HIF1α and HIF1β

Transcriptional regulation by hypoxia inducible factors

The hypoxia signaling pathway and hypoxic adaptation in fishes

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