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- Lindholm, D, et al.
(författare)
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Neuronal apoptosis inhibitory protein : structural requirements for hippocalcin binding and effects on survival of NGF-denendent sympathetic neurons
- 2002
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Ingår i: Biochimica et Biophysica Acta - Proteins and Proteomics. - : ELSEVIER SCIENCE BV. - 1570-9639 .- 1878-1454. ; 1600:1-2, s. 138-147
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Tidskriftsartikel (refereegranskat)abstract
- Neuronal apoptosis inhibitory protein (NAIP) has been linked to the inherited disease, spinal muscular atrophy (SMA), which occurs in children with degeneration of the motorneurons. In the nervous system, NAIP is expressed by specific classes of neurons including spinal -motorneurons. Recently, NAIP was shown to interact with hippocalcin, which belongs to the neuronal calcium sensor (NCS) protein family. Here we-have studied this interaction in more detail, using deletions and a mutagenesis of the third baculovirus inhibitory repeat (BIR) motif in NAIP, and functional assays for neuronal death. The results showed that specific amino acids and the zinc finger domain in BIR3 are needed for efficient interaction of NAIP with hippocalcin. Cotransfections of NAIP-BIR3 and hippocalcin resulted in translocation and colocalisation of the two proteins in neuroblastoma cells. This was accompanied by an enhanced resistance towards cell death induced by high levels of calcium. In contrast, expression of NAIP-BIR3 and hippocalcin in sympathetic neurons did not protect against death induced by nerve growth factor (NGF) withdrawal. The results demonstrate a functional interaction of hippocalcin with NAIP-BIR3, which in neuroblastoma cells leads to rescue of cells after high intracellular calcium, but which in sympathetic neurons had no significant effect. The results indicate that NAIP in conjunction with hippocalcin can affect the survival of some, but not all neural cells, and this interaction may play a role in the neurodegenerative processes in SMA, and possible other human disorders. (C) 2002 Elsevier Science B.V All rights reserved.
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| 4. |
- Yu, L Y, et al.
(författare)
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Regulation of sympathetic neuron and neuroblastoma cell death by XIAP and its association with proteasomes in neural cells
- 2003
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Ingår i: Molecular and Cellular Neuroscience. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 1044-7431 .- 1095-9327. ; 22:3, s. 308-318
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Tidskriftsartikel (refereegranskat)abstract
- XIAP (X chromosome-linked inhibitor of apoptosis protein) has been shown to inhibit cell death in a variety of cells. XIAP binds to active caspases, but XIAP also has a carboxy-terminal RING domain that can regulate cell death via protein degradation. Here we have studied the function of full-length and RING-deleted XIAP in mouse sympathetic neurons microinjected with expression plasmids and in neuroblastoma cells stably overexpressing these proteins. Both full-length and RING-deleted XIAP-protected sympathetic neurons against death induced by nerve growth factor (NGF) withdrawal to about the same extent. However, the two proteins were differentially localized in transfected neurons, with RING-deleted XIAP present in the cytoplasm and full-length XIAP found mostly in cytoplasmic protein aggregates, as revealed by transmission electron microscopy. The occurrence of these aggregates was blocked by lactacystin, a proteasome inhibitor. In neuroblastoma cells, RING-deleted XIAP protected against death induced by staurosporine, thapsigargin, or serum withdrawal, whereas full-length XIAP was without effect. Full-length, but not RING-deleted, XIAP was degraded and ubiquitinated in the neuroblastoma cells. The results show that the presence of the RING domain differentially affected the neuroprotective ability of XIAP in sensory neurons and neuroblastoma cells. The RING domain was essentially required for the proteasomal association of XIAP and for its ubiquitination. (C) 2003 Elsevier Science (USA). All rights reserved.
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