Mislocalization of human transcription factor MOK2 in the presence of pathogenic mutations of lamin A/C

Dreuillet, Caroline; Harper, Maryannick; Tillit, Jeanne; Kress, Michel; Ernoult‐Lange, Michèle

doi:10.1042/bc20070053

Cited by 25 publications

(25 citation statements)

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“…However, recent studies suggest that BAF also functions as transcriptional repressor, where it binds specific promoters [104,105]. The rod domain of human lamins A and C also binds directly to the transcription factor MOK-2 [106], and MOK-2 localization depends on lamins A and C [107]. Human lamin A also binds the SREBP-1 in vitro and this interaction is reduced when lamin A has a mutation in the Ig fold that causes familiar partial lipodystrophy [108].…”

Section: Lamins In Transcription and Splicingmentioning

confidence: 99%

Nuclear lamins: key regulators of nuclear structure and activities

Prokocimer¹,

Davidovich²,

Nissim-Rafinia³

et al. 2009

Journal of Cellular and Molecular Medicine

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Section: Lamins In Transcription and Splicingmentioning

confidence: 99%

Nuclear lamins: key regulators of nuclear structure and activities

Prokocimer¹,

Davidovich²,

Nissim-Rafinia³

et al. 2009

Journal of Cellular and Molecular Medicine

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Section: Mislocalization Through Changes In Protein Interaction or Momentioning

confidence: 99%

“…Mutations within the LMNA (lamin A/C) gene, which cause laminopathies, have recently been reported to result in mislocalization of the DNA-binding transcriptional repressor zinc finger protein 239 (ZNF239, also known as MOK2). The pathogenic lamin A/C mutant protein sequesters ZNF239 into nuclear aggregates, and this process is thought to subsequently deregulate ZNF239 target genes (Dreuillet et al, 2008).Hereditary genetic changes that alter the post-translational modifications that are relevant for correct protein localizations are also associated with human diseases. In a recent study, Cordeddu et al reported a genetic change in patients with Noonan-like syndrome that introduces an N-myristoylation site in SHOC2, a leucine-rich repeat-containing protein.…”

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confidence: 99%

Protein localization in disease and therapy

Hung

Link

2011

Journal of Cell Science

371

289

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SummaryThe eukaryotic cell is organized into membrane-covered compartments that are characterized by specific sets of proteins and biochemically distinct cellular processes. The appropriate subcellular localization of proteins is crucial because it provides the physiological context for their function. In this Commentary, we give a brief overview of the different mechanisms that are involved in protein trafficking and describe how aberrant localization of proteins contributes to the pathogenesis of many human diseases, such as metabolic, cardiovascular and neurodegenerative diseases, as well as cancer. Accordingly, modifying the disease-related subcellular mislocalization of proteins might be an attractive means of therapeutic intervention. In particular, cellular processes that link protein folding and cell signaling, as well as nuclear import and export, to the subcellular localization of proteins have been proposed as targets for therapeutic intervention. We discuss the concepts involved in the therapeutic restoration of disrupted physiological protein localization and therapeutic mislocalization as a strategy to inactivate disease-causing proteins. Journal of Cell Sciencecompartment has been associated with human diseases, and in the following sections we will discuss some of the mechanisms that can lead to such changes in protein localization. Mislocalization through alterations of the protein trafficking machineryDysregulation of the protein trafficking machinery can have dramatic effects on general protein transport processes, modifying cell morphology and physiology. Along these lines, changes in the nuclear pore complex (NPC) have been linked to several genetic disorders (Chahine and Pierce, 2009). For example, in patients with familial atrial fibrillation, the homozygous mutation R391H in the nucleoporin NUP155 has been shown to reduce nuclear envelope permeability and affect the export of Hsp70 mRNA and import of HSP70 protein (Zhang et al., 2008). That study was the first to link a nucleoporin defect to cardiovascular disease.Mutations in other components of the NPC, such as the nucleoporin p62 protein and ALADIN (alacrima achalasia adrenal insufficiency neurologic disorder, officially known as AAAS) are thought to cause the neurodegenerative diseases infantile bilateral striatal necrosis and triple A syndrome, respectively (Basel-Vanagaite et al., 2006; Kiriyama et al., 2008). Mutant ALADIN prevents nuclear entry of the DNA repair proteins aprataxin and DNA ligase I and, therefore, results in increased DNA damage and subsequent cell death caused by oxidative stress (Kiriyama et al., 2008). In a similar fashion, protein import into other organelles can be affected by mutations in the trafficking machinery. For instance, mutations in the peroxin gene PEX7, which encodes a peroxisomal import receptor that is responsible for the transport of several essential peroxisomal enzymes, have been found to cause the peroxisome biogenesis disorder rhizomelic chondrodysplasia punctata type 1 (RCDP1) (Braverman e...

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“…Crude protein extracts were prepared and purified as described previously (Dreuillet et al 2008). The GST fusion proteins bound to glutathione beads were used as 50% slurry in the appropriate buffer.…”

Section: Preparation Of Recombinant Proteins In E Colimentioning

confidence: 99%

Multiple binding of repressed mRNAs by the P-body protein Rck/p54

Ernoult‐Lange

Baconnais

Harper

et al. 2012

RNA

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107

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Translational repression is achieved by protein complexes that typically bind 39 UTR mRNA motifs and interfere with the formation of the cap-dependent initiation complex, resulting in mRNPs with a closed-loop conformation. We demonstrate here that the human DEAD-box protein Rck/p54, which is a component of such complexes and central to P-body assembly, is in considerable molecular excess with respect to cellular mRNAs and enriched to a concentration of 0.5 mM in P-bodies, where it is organized in clusters. Accordingly, multiple binding of p54 proteins along mRNA molecules was detected in vivo. Consistently, the purified protein bound RNA with no sequence specificity and high nanomolar affinity. Moreover, bound RNA molecules had a relaxed conformation. While RNA binding was ATP independent, relaxing of bound RNA was dependent on ATP, though not on its hydrolysis. We propose that Rck/p54 recruitment by sequence-specific translational repressors leads to further binding of Rck/p54 along mRNA molecules, resulting in their masking, unwinding, and ultimately recruitment to P-bodies. Rck/p54 proteins located at the 59 extremity of mRNA can then recruit the decapping complex, thus coupling translational repression and mRNA degradation.

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Mislocalization of human transcription factor MOK2 in the presence of pathogenic mutations of lamin A/C

Cited by 25 publications

References 45 publications

Nuclear lamins: key regulators of nuclear structure and activities

Nuclear lamins: key regulators of nuclear structure and activities

Protein localization in disease and therapy

Multiple binding of repressed mRNAs by the P-body protein Rck/p54

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