Apoptosis Research Center

Gaillimh, Ireland

Apoptosis Research Center

Gaillimh, Ireland
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van Vliet A.R.,Catholic University of Leuven | Giordano F.,University Paris Diderot | Gerlo S.,Vlaams Institute for Biotechnology | Segura I.,Catholic University of Leuven | And 16 more authors.
Molecular Cell | Year: 2017

Loss of ER Ca2+ homeostasis triggers endoplasmic reticulum (ER) stress and drives ER-PM contact sites formation in order to refill ER-luminal Ca2+. Recent studies suggest that the ER stress sensor and mediator of the unfolded protein response (UPR) PERK regulates intracellular Ca2+ fluxes, but the mechanisms remain elusive. Here, using proximity-dependent biotin identification (BioID), we identified the actin-binding protein Filamin A (FLNA) as a key PERK interactor. Cells lacking PERK accumulate F-actin at the cell edges and display reduced ER-PM contacts. Following ER-Ca2+ store depletion, the PERK-FLNA interaction drives the expansion of ER-PM juxtapositions by regulating F-actin-assisted relocation of the ER-associated tethering proteins Stromal Interaction Molecule 1 (STIM1) and Extended Synaptotagmin-1 (E-Syt1) to the PM. Cytosolic Ca2+ elevation elicits rapid and UPR-independent PERK dimerization, which enforces PERK-FLNA-mediated ER-PM juxtapositions. Collectively, our data unravel an unprecedented role of PERK in the regulation of ER-PM appositions through the modulation of the actin cytoskeleton. van Vliet et al. show that the actin regulator FLNA interacts with the ER stress kinase PERK and that this interaction is required for the efficient formation of ER-plasma membrane contact sites. This function of PERK is independent of the UPR and is activated by ER Ca2+ store depletion. © 2017 Elsevier Inc.


Kennedy D.,Apoptosis Research Center | Jager R.,Bonn-Rhein-Sieg University of Applied Sciences | Mosser D.D.,University of Guelph | Samali A.,Apoptosis Research Center
IUBMB Life | Year: 2014

Thermotolerance, the acquired resistance of cells to stress, is a well-established phenomenon. Studies of the key mediators of this response, the heat shock proteins (HSPs), have led to the discovery of the important roles played by these proteins in the regulation of apoptotic cell death. Apoptosis is critical for normal tissue homeostasis and is involved in diverse processes including development and immune clearance. Apoptosis is tightly regulated by both proapoptotic and antiapoptotic factors, and dysregulation of apoptosis plays a significant role in the pathophysiology of many diseases. In the recent years, HSPs have been identified as key determinants of cell survival, which can modulate apoptosis by directly interacting with components of the apoptotic machinery. Therefore, manipulation of the HSPs could represent a viable strategy for the treatment of diseases. Here, we review the current knowledge with regard to the mechanisms of HSP-mediated regulation of apoptosis. © 2014 International Union of Biochemistry and Molecular Biology.


Chakravarthy R.,Apoptosis Research Center | Mnich K.,Apoptosis Research Center | Gorman A.M.,Apoptosis Research Center
Biochemical and Biophysical Research Communications | Year: 2016

Triple negative breast cancer [TNBC] cells are reported to secrete the neurotrophin nerve growth factor [NGF] and express its receptors, p75 neurotrophin receptor [p75NTR] and TrkA, leading to NGF-activated pro-survival autocrine signaling. This provides a rationale for NGF as a potential therapeutic target for TNBC. Here we show that exposure of TNBC cells to NGF leads to increased levels of p75NTR, which was diminished by NGF-neutralizing antibody or NGF inhibitors [Ro 08-2750 and Y1086]. NGF-mediated increase in p75NTR levels were partly due to increased transcription and partly due to inhibition of proteolytic processing of p75NTR. In contrast, proNGF caused a decrease in p75NTR levels. Functionally, NGF-induced increase in p75NTR caused a decrease in the sensitivity of TNBC cells to apoptosis induction. In contrast, knock-down of p75NTR using shRNA or small molecule inhibition of NGF-p75NTR interaction [using Ro 08-2750] sensitized TNBC cells to drug-induced apoptosis. In patient samples, the expression of NGF and NGFR [the p75NTR gene] mRNA are positively correlated in several subtypes of breast cancer, including basal-like breast cancer. Together these data suggest a positive feedback loop through which NGF-mediated upregulation of p75NTR can contribute to the chemo-resistance of TNBC cells. © 2016 Elsevier Inc.


PubMed | Apoptosis Research Center
Type: Journal Article | Journal: Biochemical and biophysical research communications | Year: 2016

Triple negative breast cancer [TNBC] cells are reported to secrete the neurotrophin nerve growth factor [NGF] and express its receptors, p75 neurotrophin receptor [p75(NTR)] and TrkA, leading to NGF-activated pro-survival autocrine signaling. This provides a rationale for NGF as a potential therapeutic target for TNBC. Here we show that exposure of TNBC cells to NGF leads to increased levels of p75(NTR), which was diminished by NGF-neutralizing antibody or NGF inhibitors [Ro 08-2750 and Y1086]. NGF-mediated increase in p75(NTR) levels were partly due to increased transcription and partly due to inhibition of proteolytic processing of p75(NTR). In contrast, proNGF caused a decrease in p75(NTR) levels. Functionally, NGF-induced increase in p75(NTR) caused a decrease in the sensitivity of TNBC cells to apoptosis induction. In contrast, knock-down of p75(NTR) using shRNA or small molecule inhibition of NGF-p75(NTR) interaction [using Ro 08-2750] sensitized TNBC cells to drug-induced apoptosis. In patient samples, the expression of NGF and NGFR [the p75(NTR) gene] mRNA are positively correlated in several subtypes of breast cancer, including basal-like breast cancer. Together these data suggest a positive feedback loop through which NGF-mediated upregulation of p75(NTR) can contribute to the chemo-resistance of TNBC cells.

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