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G-protein pathway suppressor 2 protein induces cell death by activating caspase-3 and inhibits XIAP in vitro
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Neurobiology.
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Manuscript (Other academic)
Identifiers
URN: urn:nbn:se:uu:diva-97221OAI: oai:DiVA.org:uu-97221DiVA: diva2:172059
Available from: 2008-05-06 Created: 2008-05-06 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Novel Interactors of X-linked Inhibitor of Apoptosis Protein: Expression and Effects on Tumor Cell Death
Open this publication in new window or tab >>Novel Interactors of X-linked Inhibitor of Apoptosis Protein: Expression and Effects on Tumor Cell Death
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Programmed cell death, or apoptosis, has during the last decade received a lot of attention due to its involvement in a large number of pathological conditions. Since death is always irreversible, it is important for cells to fully control the initiation and execution of this process. One of many apoptosis-regulatory proteins is XIAP, which blocks the action of caspases, a family of proteases that are important during apoptosis. However, apoptosis inhibitors have to be tightly controlled since too little cell death can lead to the development of tumors and other diseases. This thesis is the result of an aspiration to fully understand the function and regulation of XIAP.

By using the yeast-2-hybrid system, we identified two novel binding partners of XIAP. The first, GPS2, was found to bind XIAP and inhibit its ability to block caspase-activity. In addition, GPS2 induced caspase-mediated cell death in two different tumour cell lines and XIAP inhibited this effect.

The second binding partner, Nulp1, preferentially bound XIAP in the presence of the apoptosis-inducer staurosporine. Nulp1 induced or sensitized cell lines to cell death when overexpressed, but this was not blocked by caspase-inhibitors or XIAP, suggesting a different reason for binding than apoptosis regulation. With the aim to understand the Nulp1-XIAP interaction, we continued to study Nulp1 in vivo and in vitro. We studied three different splice variants of Nulp1 and found that they were regulated by poly-ubiquitination and nuclear shuttling. Also, Nulp1 was expressed in embryonic mice, especially in the cortical plate, hippocampal neurons and cerebellar granular neurons. Expression of Nulp1 decreased with age but was still present in cerebellar deep nuclei and Purkinje cells of adult mice.

To summarize, we have identified GPS2 as an apoptosis-inducing factor and an inhibitor of XIAP in vitro, and Nulp1 as a XIAP-interacting protein during staurosporine-induced apoptosis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 64 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 353
Keyword
Neurobiology, XIAP, tumor cell death, apoptosis, caspases, basic helix-loop-helix protein, Neurobiologi
Identifiers
urn:nbn:se:uu:diva-8742 (URN)978-91-554-7203-0 (ISBN)
Public defence
2008-05-27, B42, BMC, Husargatan 3, Uppsala, 09:15
Opponent
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Available from: 2008-05-06 Created: 2008-05-06Bibliographically approved

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