Bcl-2 expression regulates cell sensitivity to S100beta-mediated apoptosis.
The S100beta protein is overexpressed in the brain of patients with Alzheimer's disease and Down's syndrome and is able to induce apoptosis in neurons at high concentrations. The intracellular events that regulate the apoptotic effect are largely unknown. This study investigates the roles of the bcl-2 proto-oncogene, one of the best-defined apoptotic genes, on cell death induced by S100beta. Human neuronal precursor NT2/D1 cells showed a high degree of cell death by apoptosis after exposure to 2 microM S100beta in serum-free medium. Death was preceded by a down-regulation of the Bcl-2 protein. Gene transfer with a full-length bcl-2 cDNA under the control of a constitutive promoter in NT2 cells elevated Bcl-2 protein levels and repressed S100beta-mediated cell death. When exposed to retinoic acid, the NT2/D1 cells differentiated into a neuronal phenotype. The differentiated cells up-regulated their levels of Bcl-2 and became resistant to S100beta-induced cell death. Downregulation of Bcl-2 by an antisense oligonucleotide in the differentiated cells, however, increased their susceptibility to S100beta-related cytotoxicity. Therefore, apoptosis induced through S100beta signaling is subject to regulation by Bcl-2. A combined alteration such as up-regulation of S100beta together with down-regulation of Bcl-2 may be important in the pathogenesis of Alzheimer's disease and Down's syndrome.
Wang
S
S
Department of Anatomy and Cell Biology, Göteborg University, Medicinaregatan 5, 413 90, Göteborg, Sweden. shu.wang@anatcell.gu.se
Rosengren
L E
LE
Franlund
M
M
Hamberger
A
A
Haglid
K G
KG
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000494:pharmacology*; D016895:Culture Media, Serum-Free; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D019254:Genes, bcl-2; D006801:Humans; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D020033:Protein Isoforms / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000502:physiology*; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins
D002135:Calcium-Binding Proteins; D016895:Culture Media, Serum-Free; C000715470:MAS1 protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D016376:Oligonucleotides, Antisense; D020033:Protein Isoforms; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins