Elk-1 associates with the mitochondrial permeability transition pore complex in neurons

Barrett, Lindy E.; Bockstaele, E. J. Van; Sul, Jai‐Yoon; Takano, Hajime; Haydon, Philip G.; Eberwine, Jim

doi:10.1073/pnas.0510477103

Cited by 52 publications

(60 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The phosphorylation-dependent trafficking of Elk-1 to the nucleus is a major observation because, within the cytoplasm, Elk-1 is associated with the mitochondrial PTP (Permeability Transition Pore complex), an interaction that increases in the context of proapoptotic treatments (Barrett and al., 2006b). Furthermore, restricting Elk-1 transcription and translation in neurites, using a focal transfection procedure named "phototransfection", produces cell death, whereas its introduction and translation in cell bodies does not (Barrett et al, 2006a).…”

Section: Discussionmentioning

confidence: 99%

A TAT–DEF–Elk-1 Peptide Regulates the Cytonuclear Trafficking of Elk-1 and Controls Cytoskeleton Dynamics

Lavaur¹,

Bernard²,

Trifilieff³

et al. 2007

J. Neurosci.

View full text Add to dashboard Cite

The transcription factor Elk-1 plays a key role in cell differentiation, proliferation and apoptosis. This role is thought to arise from its phosphorylation by activated extracellular signal-regulated kinases (ERKs), a critical posttranslational event for the transcriptional activity of the ternary complex composed of Elk-1 and a dimer of serum response factor (SRF) at the serum response element (SRE) regulatory site of transcription. In addition to its nuclear localization, Elk-1 is found in the dendrites and soma of neuronal cells and recent evidence implicate a cytoplasmic proapoptotic function of Elk-1, via its association with the mitochondrial permeability transition pore complex. Thus, the nuclear versus cytoplasmic localization of Elk-1 seems to be crucial for its biological function. In this study we show that the excitatory neurotransmitter, glutamate, induces an ERK-dependent Elk-1 activation and nuclear relocalization. We demonstrate that Elk-1 phosphorylation on Ser383/389 has a dual function and triggers both Elk-1 nuclear translocation and SRE-dependent gene expression. Mutating these sites into inactive residues or using a synthetic penetrating peptide (TAT-DEF-Elk-1), which specifically interferes with the DEF docking domain of Elk-1, prevents Elk-1 nuclear translocation without interfering with ERK nor MSK1 (mitogenand stress-activated protein kinase 1), a CREB kinase downstream from ERK-activation. This results in a differential regulation of glutamate-induced IEG regulation when compared with classical inhibitors of the ERK pathway. Using the TAT-DEF-Elk-1 peptide or the dominant-negative version of Elk-1, we show that Elk-1 phosphorylation controls dendritic elongation, SRF and Actin expression levels as well as cytoskeleton dynamics.

show abstract

Section: Discussionmentioning

confidence: 99%

A TAT–DEF–Elk-1 Peptide Regulates the Cytonuclear Trafficking of Elk-1 and Controls Cytoskeleton Dynamics

Lavaur¹,

Bernard²,

Trifilieff³

et al. 2007

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Protein content of the resultant cytosolic supernatant was measured. Alternatively, in some experiments mitochondria were prepared with the Pierce isolation kit (64,65), and their protein content was determined. Aliquots of mitochondrial and cytosolic protein were analyzed by SDS-PAGE and immunoblotted with antibodies to cytochrome c (Santa Cruz Biotechnology, Santa Cruz, CA), tubulin, iPLA 2 ␤ (antibody 509 from Dr. Richard Gross, Washington University), and the mitochondrial marker cytochrome c oxidase complex IV-subunit II (Molecular Probes, Eugene, OR) (64).…”

Section: Methodsmentioning

confidence: 99%

Attenuated Free Cholesterol Loading-induced Apoptosis but Preserved Phospholipid Composition of Peritoneal Macrophages from Mice That Do Not Express Group VIA Phospholipase A2

Bao

Lei

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

Mouse macrophages undergo ER stress and apoptosis upon free cholesterol loading (FCL). We recently generated iPLA 2 ␤-null mice, and here we demonstrate that iPLA 2 ␤-null macrophages have reduced sensitivity to FCL-induced apoptosis, although they and wild-type (WT) cells exhibit similar increases in the transcriptional regulator CHOP. iPLA 2 ␤-null macrophages are also less sensitive to apoptosis induced by the sarcoplasmic reticulum Ca 2؉ -ATPase inhibitor thapsigargin and the scavenger receptor A ligand fucoidan, and restoring iPLA 2 2 ␤ modulates mitochondrial cytochrome c release, and we find that thapsigargin and fucoidan induce mitochondrial phospholipid loss and cytochrome c release into WT macrophage cytosol and that these events are blunted in iPLA 2 ␤-null cells. Immunoblotting studies indicate that iPLA 2 ␤ associates with mitochondria in macrophages subjected to ER stress. AA incorporation into glycerophosphocholine lipids is unimpaired in iPLA 2 ␤-null macrophages upon electrospray ionization-tandem mass spectrometry analyses, and their complex lipid composition is similar to WT cells. These findings suggest that iPLA 2 ␤ participates in ER stress-induced macrophage apoptosis caused by FCL or thapsigargin but that deletion of iPLA 2 ␤ does not impair macrophage arachidonate incorporation or phospholipid composition.

show abstract

“…Numbers under the blots represent VDAC-normalized changes in mitochondrial Elk-1 phosphorylation from four independent experiments. neurons exposed to DNA damage (Barrett et al, 2006) led us to investigate whether A␤ induces Elk-1 association with mitochondria and causes mitochondrial dysfunction. We found that A␤ increases the level of Elk-1 at mitochondria isolated from dissociated hippocampal neurons (Fig.…”

Section: Elk-1 Association With Mitochondria Is Involved In A␤-mediatmentioning

confidence: 99%

“…Extranuclear Elk-1 associates with mPTP in apoptotic neurons (Barrett et al, 2006) and has been implicated in neurodegenerative diseases including AD (Sharma et al, 2010). Because both CentA1 and Elk-1 can associate with mPTP and regulate its function (Barrett et al, 2006;Galvita et al, 2009) In this study, we show that the CentA1-Ras-Elk-1 pathway links A␤ and synaptic dysfunction. We found that A␤ upregulates CentA1 and activates the Ras-Elk-1 pathway at mitochondria, which impairs mitochondrial activity.…”

Section: Introductionmentioning

confidence: 99%

Centaurin-α1-Ras-Elk-1 Signaling at Mitochondria Mediates β-Amyloid-Induced Synaptic Dysfunction

et al. 2013

View full text Add to dashboard Cite

Alzheimer's disease is thought to be caused by ␤-amyloid peptide (A␤)-dependent synaptic dysfunction. However, the signaling pathways connecting A␤ and synaptic dysfunction remain elusive. Here we report that A␤ transiently increases the expression level of centaurin-␣1 (CentA1) in neurons, which induces a Ras-dependent association of Elk-1 with mitochondria, leading to mitochondrial and synaptic dysfunction in organotypic hippocampal slices of rats. Downregulation of the CentA1-Ras-Elk-1 pathway restored normal mitochondrial activity, spine structural plasticity, spine density, and the amplitude and frequency of miniature EPSCs in A␤-treated neurons, whereas upregulation of the pathway was sufficient to decrease spine density. Elevations of CentA1 and association of Elk-1 with mitochondria were also observed in transgenic mice overexpressing a human mutant form of amyloid precursor protein. Therefore, the CentA1-Ras-Elk-1 signaling pathway acts on mitochondria to regulate dendritic spine density and synaptic plasticity in response to A␤ in hippocampal neurons, providing new pharmacological targets for Alzheimer's disease.

show abstract

Elk-1 associates with the mitochondrial permeability transition pore complex in neurons

Cited by 52 publications

References 33 publications

A TAT–DEF–Elk-1 Peptide Regulates the Cytonuclear Trafficking of Elk-1 and Controls Cytoskeleton Dynamics

A TAT–DEF–Elk-1 Peptide Regulates the Cytonuclear Trafficking of Elk-1 and Controls Cytoskeleton Dynamics

Attenuated Free Cholesterol Loading-induced Apoptosis but Preserved Phospholipid Composition of Peritoneal Macrophages from Mice That Do Not Express Group VIA Phospholipase A2

Centaurin-α1-Ras-Elk-1 Signaling at Mitochondria Mediates β-Amyloid-Induced Synaptic Dysfunction

Contact Info

Product

Resources

About