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Increased spatiotemporal resolution of caspase activation by anchoring FRET-based sensors to cytoskeleton
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.ORCID-id: 0000-0002-1007-747X
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.ORCID-id: 0000-0003-1476-6675
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.ORCID-id: 0000-0003-2092-457X
Vise andre og tillknytning
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
Emneord [en]
AFS, Apoptosis, Caspases, FRET, Live Cell Imaging
HSV kategori
Forskningsprogram
neurokemi med molekylär neurobiologi
Identifikatorer
URN: urn:nbn:se:su:diva-79138OAI: oai:DiVA.org:su-79138DiVA, id: diva2:547701
Forskningsfinansiär
Swedish Research CouncilTilgjengelig fra: 2012-08-28 Laget: 2012-08-28 Sist oppdatert: 2016-01-29bibliografisk kontrollert
Inngår i avhandling
1. Regulation of apoptotic processes in neurodegeneration and cancer: In vitro studies on human neuroblastoma cells
Åpne denne publikasjonen i ny fane eller vindu >>Regulation of apoptotic processes in neurodegeneration and cancer: In vitro studies on human neuroblastoma cells
2012 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Apoptosis is a highly controlled process of cell death, which is vital for maintenance of all multicellular organisms. Aberrant regulation of apoptosis can give rise to pathological conditions such as neurodegenerative diseases and cancer. Here, we used different human neuroblastoma cell lines to study mechanisms that may be involved in either neurodegeneration or resistance to cancer treatment. First, we have designed and developed tau-anchored FRET sensors (tAFSs) for live cell imaging of local caspase activation. Using these sensors we showed that the Alzheimer’s disease related neurotoxic peptide, amyloid-β, induced a global activation of caspase-3 and -6, but not -9, in neuronally differentiated SH-SY5Y cells. We also investigated the possible role of NF-κB in the resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in different human neuroblastoma cell lines. While N-type SH-SY5Y and IMR32 cells were unaffected, S-type SK-N-AS cells were clearly sensitized to TRAIL by different NF-κB inhibitory agents. However, no correlation between NF-κB inhibition and sensitization to TRAIL could be observed. Instead, induction of reactive oxygen species (ROS) seemed to play a more important role. Furthermore, using tAFSs we also showed that TRAIL resistance in SK-N-AS cells is mainly due to incomplete activation of caspase-3, and could be reversed by different PKC inhibitors.

sted, utgiver, år, opplag, sider
Stockholm: Department of Neurochemistry, Stockholm University, 2012. s. 71
HSV kategori
Forskningsprogram
neurokemi med molekylär neurobiologi
Identifikatorer
urn:nbn:se:su:diva-79157 (URN)978-91-7447-553-1 (ISBN)
Disputas
2012-10-19, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 13:00 (engelsk)
Opponent
Veileder
Merknad

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 2: Manuscript.

Tilgjengelig fra: 2012-09-27 Laget: 2012-08-28 Sist oppdatert: 2019-05-27bibliografisk kontrollert
2. Caspase activation in human neuroblastoma cells: mechanisms and spatiotemporal aspects
Åpne denne publikasjonen i ny fane eller vindu >>Caspase activation in human neuroblastoma cells: mechanisms and spatiotemporal aspects
2015 (engelsk)Licentiatavhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Apoptosis is one of the modes of programmed cell death, in which several members of the caspase family of proteases play the central role. However, activation of apoptotic caspases does not necessarily lead to cell death. Instead, these caspases may mediate, for instance, differentiation or synaptic plasticity, if their activity is restricted in space and time. Such localized caspase activation has been also implicated in the initial stages of neurodegeneration. In order to assess this kind of events at a subcellular level, our research group has previously constructed tau-anchored FRET-based caspase sensors (tAFSs). Here, we demonstrate that localization of tAFSs to the cytoskeleton results in enrichment of the sensors in neuritic processes and enables increased spatiotemporal resolution for live cell imaging of caspase activation, as compared to soluble FRET sensors. This feature is particularly beneficial for investigation of neurodegeneration-related processes.

tAFSs were further employed for investigation of caspase activation in neuroblastoma, an extracranial solid pediatric tumor. Tumor necrosis factor-related apoptosis inducing factor (TRAIL) is a promising candidate for cancer treatment due to its ability to selectively trigger apoptosis malignant cells. However, many cancer cells, including neuroblastoma, acquire resistance to TRAIL. Here, we show that in S-type neuroblastoma cell lines, TRAIL resistance is dependent on incomplete activation of apoptotic caspase-3. Sensitization to TRAIL was achieved with protein kinase C (PKC)-inhibiting compounds, suggesting a role for this kinase in blocking the apoptotic response to TRAIL. This effect of PKC could possibly involve stabilization of XIAP, an endogenous caspase inhibitor, as PKC inhibition, in combination with TRAIL treatment, led to downregulation of XIAP.

sted, utgiver, år, opplag, sider
Stockholm: Department of Neurochemistry, 2015
Emneord
apoptosis, caspase, local caspase activation, neurodegeneration, tau-anchored FRET sensors, tAFS, cancer, neuroblastoma, TNF-related apoptosis inducing ligand, TRAIL, protein kinase C, PKC, X-linked inhibitor of apoptosis protein, XIAP
HSV kategori
Forskningsprogram
neurokemi med molekylär neurobiologi
Identifikatorer
urn:nbn:se:su:diva-122651 (URN)978-91-7649-303-8 (ISBN)
Presentation
2015-11-27, Heilbronnsalen, C458, Svante Arrhenius väg 16B, Stockholm, 14:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2015-11-12 Laget: 2015-11-05 Sist oppdatert: 2015-11-12bibliografisk kontrollert

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