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- Hamnér, Susanne
(författare)
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Studies on the Bcl-2 Family of Apoptosis Regulators in the Nervous System
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Apoptosis is a type of cell death with a specific morphology and molecular program, which is essential for the development of the nervous system. However, inappropriate cell death has been implicated in several neurodegenerative diseases. The Bcl-2 protein family is a class of proteins, which can regulate the cell death program in either a positive (pro-apoptotic family members) or a negative (anti-apoptotic family members) way. This thesis further elucidates the role of Bcl-2 family members in the nervous system. Special focus has been put on the anti-apoptotic family member Bcl-w, whose function in the nervous system was previously unknown, and the pro-apoptotic family member Bad which serves as a link between growth factor signalling and apoptosis. Bcl-w mRNA was found to be upregulated during rat brain development suggesting increasing importance of Bcl-w with age in the nervous system. In contrast, mRNA levels encoding the anti-apoptotic protein Bcl-x were downregulated during development. Bcl-w was also found to have an anti-apoptotic function in neurons, rescuing sympathetic neurons from cell death after nerve growth factor deprivation. To further elucidate the mechanism by which Bcl-w exerts its function, we screened a yeast two-hybrid library for proteins interacting with Bcl-w. Two of the isolated positive clones encoded the pro-apoptotic protein Bad and a novel splice variant of Bad with a different carboxyterminal sequence. Both isoforms of Bad induced cell death in sympathetic neurons, which could be counteracted by Bcl-w, indicating that Bcl-w and Bad can interact both physically and functionally. Further studies on the genomic structure of the Bad gene suggested the presence of an additional splice variant, not expressing the first exon. Immunohistochemical analysis indicates that the isoform(s) not expressing the first exon is more widely expressed in adult rat brain than the known forms. Finally, we show that high cell density can enhance survival of cerebellar granule neurons and that bcl-2 and bcl-x mRNA levels are upregulated in high density cultures.
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- Korhonen, Laura, et al.
(författare)
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Bcl-2 regulates the levels of the cysteine proteases ICH and CPP32/Yama in human neuronal precursor cells
- 1997
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Ingår i: European Journal of Neuroscience. - Univ Uppsala, Ctr Biomed, Dept Dev Neurosci, S-75123 Uppsala, Sweden. : Wiley-Blackwell Publishing Inc.. - 0953-816X .- 1460-9568. ; 9:11, s. 2489-2496
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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