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Nuclear localized protein-1 (Nulp1) increases cel death of human osteosarcoma cells and binds the X-linked inhibitor of apoptosis protein
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
2008 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, ISSN 0006-291X, Vol. 366, no 2, 432-437 p.Article in journal (Refereed) Published
Abstract [en]

Nuclear localized protein-1 (Nulp1) is a recently identified gene expressed in mouse and human tissues particularly during embryonic development. Nulp1 belongs to the family of basic helix-loop-helix (bHLH) proteins that are important in development. The precise function of Nulp1 in cells is however not known. We observed that overexpression of Nulp1 induces a large increase in cell death of human osteosarcoma Saos2 cells with DNA fragmentation. In mouse N2A neuroblastoma cells Nulp1 affected cell proliferation and sensitized cells towards death induced by staurosporine. Staining using a novel antibody localized Nulp1 mainly to the cell nucleus and to some extent to the cytoplasm. Nulp1 binds the X-linked inhibitor of apoptosis protein (XIAP) and this interaction was increased during cell death. These results indicate that Nulp1 plays a role in cell death control and may influence tumor growth.

Place, publisher, year, edition, pages
2008. Vol. 366, no 2, 432-437 p.
Keyword [en]
Nulp1, Cell death, XIAP, Tumor cells
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97222DOI: 10.1016/j.bbrc.2007.11.146ISI: 000252436300026PubMedID: 18068114OAI: oai:DiVA.org:uu-97222DiVA: diva2:172060
Available from: 2008-05-06 Created: 2008-05-06 Last updated: 2017-12-14Bibliographically 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
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Supervisors
Available from: 2008-05-06 Created: 2008-05-06Bibliographically approved

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