Bcl-2 and p53: role in dopamine-induced apoptosis and differentiation.
The fate of a neuron in the developing brain to multiply, differentiate, or die in an apoptotic manner depends on the expression of genes that are involved in regulating the cell cycle. Recent studies determined the involvement of several genes, including cyclin A and B2, in dopamine-induced apoptosis in cultured chick sympathetic neurons. Another gene that plays a role in apoptosis and differentiation of neurons, oligodendrocytes and PC12 cells is p53. It is also known that DNA damage increases p53 levels, triggering repair or apoptosis in response to moderate or severe damage, respectively. NMB cells express active and inducible forms of p53, thus being particularly suitable to analyze the role of this gene in dopamine-induced apoptosis and differentiation. The main observation of this work is that low concentrations of dopamine induce differentiation while high concentrations induce apoptosis, and that concentrations of dopamine that induce apoptosis increased p53 levels. There peak increase in p53 was within 3-6 h, before cell death. Thus, treatment with a high dopamine concentration may result in oxidation products and/or free radicals that heavily damage DNA, thus increasing p53 levels and initiating a cascade of events leading to apoptosis. Lower concentrations of dopamine apparently have a milder damaging effect on the DNA and induce growth arrest and differentiation. In various systems Bcl-2 inhibits cell death, being apoptotic or necrotic. Bcl-2, and other members of the family, such as Bax, are located downstream to p53 in the apoptotic pathway, and they contain negative or positive p53 response elements. Bcl-2 also protects cells by acting as antioxidant. Neuronal differentiation may be accompanied with an increase in Bcl-2, though it was suggested that the role of Bcl-2 in differentiation is less critical than in apoptosis. Herein, Bcl-2 was found to inhibit dopamine neurotoxicity. Whether the expression of Bcl-2 is regulated by different dopamine concentrations, or by dibutyryl-cAMP and DMSO, remains to be determined.
Porat
S
S
Department of Moleculr Genetics, Weizmann Institute, Rehovot, Israel.
Simantov
R
R
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D003994:Bucladesine / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology*; D006801:Humans; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D003994:Bucladesine; D004298:Dopamine; D004121:Dimethyl Sulfoxide