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Bcl-2 regulates the levels of the cysteine proteases ICH and CPP32/Yama in human neuronal precursor cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
1997 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 9, no 11, 2489-2496 p.Article in journal (Refereed) Published
Abstract [en]

Members of the Bcl-2 family are major regulators of cell death and survival. Bcl-2 has been shown to heterodimerize with the death-inducing protein Bax, but the mechanism of action of Bcl-2 is not fully understood. Here we show, using the human NT-2 neuronal cell line, that overexpression of Bcl-2 leads to dramatic down-regulation of the cysteine proteases ICH and CPP32/Yama, which are directly involved in cell death. In addition, the nuclear enzyme poly(ADP-ribose) polymerase was cleaved in control cells but not in cells overexpressing Bcl-2 following induction of apoptosis. The mRNA levels of ICH and CPP32/Yama were differentially affected by Bcl-2 overexpression, suggesting both transcriptional and post-transcriptional effects of the protein. These results demonstrate novel mechanisms of action of Bcl-2 in influencing the expression of death effectors such as the cysteine proteases. The relative levels of Bcl-2 and of various cysteine proteases ultimately determine survival and death of different cells, including neurons.

Place, publisher, year, edition, pages
1997. Vol. 9, no 11, 2489-2496 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-89653DOI: 10.1111/j.1460-9568.1997.tb01666.xPubMedID: 9464943OAI: oai:DiVA.org:uu-89653DiVA: diva2:161318
Available from: 2002-02-15 Created: 2002-02-15 Last updated: 2013-06-13Bibliographically approved
In thesis
1. Anti-Apoptotic Proteins in Nerve Cell Survival and Neurodegeneration
Open this publication in new window or tab >>Anti-Apoptotic Proteins in Nerve Cell Survival and Neurodegeneration
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Apoptosis is a genetically regulated cell death program, which shows distinct morphological characteristics. It takes place during neuronal development and in some neurodegenerative diseases. During apoptosis, the intracellular proteins are degraded by various caspases, cysteine aspartases, which are regulated by pro- and anti-apoptotic signals. This thesis elucidates the role of anti-apoptotic proteins in nerve cell survival and neurodegeneration. Studies have focused on Bcl-2 family members and Inhibitor of Apoptosis Proteins (IAP).

XIAP and RIAP-2 are IAP proteins, which are expressed by neurons in the central nervous system. Kainic acid, a glutamate receptor agonist that induces seizures, increased XIAP immunoreactivity in rat hippocampus, whereas RIAP-2 expression in the same time decreased in degenerating neurons. Both XIAP and RIAP-2 were absent in dying neurons indicating that these proteins have a protective role in kainic acid induced neurodegeneration.

NAIP, another IAP family member, was shown to interact with the calcium binding protein Hippocalcin using the yeast two-hybrid system and immunoprecipitation experiments. Hippocalcin-NAIP interaction increased motoneuron survival in caspase-3 independent and dependent manners.

The anti-apoptotic Bcl-2 proteins, Bcl-2 and Bcl-x, were studied using cultured neurons and human neuronal progenitor cells. In the progenitor cells, Bcl-2 overexpression enhanced cell survival and induced downregulation of Caspase-2 (ICH-1) and caspase-3 (YAMA/CPP32). These results suggest a novel mechanism for the action of Bcl-2.

Estrogen was shown to inhibit death of cultured dorsal root ganglion neurons (DRG) after nerve growth factor withdrawal. The hormone increased the levels of Bcl-x, which may explain the known neuroprotective function of estrogen.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2002. 65 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1120
Keyword
Neurosciences, neuronal cell death, XIAP, RIAP-2, Hippocalcin, Bcl-2, Bcl-X, kainic acid, DRG, estrogen, Neurovetenskap
National Category
Neurology
Research subject
Developmental Neurosciences
Identifiers
urn:nbn:se:uu:diva-1752 (URN)91-554-5230-2 (ISBN)
Public defence
2002-03-08, Uppsala Biomedical Centre (BMC), lecture room B22, Uppsala, 09:15
Opponent
Available from: 2002-02-15 Created: 2002-02-15Bibliographically approved

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