Abstract
DP5, which contains a BH3 domain, was cloned as a neuronal apoptosis-inducing gene. To confirm that DP5 interacts with members of the Bcl-2 family, 293T cells were transiently co-transfected with DP5 and Bcl-xl cDNA constructs, and immunoprecipitation was carried out. The 30-kDa Bcl-xl was co-immunoprecipitated with Myc-tagged DP5, suggesting that DP5 physically interacts with Bcl-xl in mammalian cells. Previously, we reported that DP5 is induced during neuronal apoptosis in cultured sympathetic neurons. Here, we analyzed DP5 gene expression and the specific interaction of DP5 with Bcl-xl during neuronal death induced by amyloid-beta protein (A beta). DP5 mRNA was induced 6 h after treatment with A beta in cultured rat cortical neurons. The protein encoded by DP5 mRNA showed a specific interaction with Bcl-xl. Induction of DP5 gene expression was blocked by nifedipine, an inhibitor of L-type voltage-dependent calcium channels, and dantrolene, an inhibitor of calcium release from the endoplasmic reticulum. These results suggested that the induction of DP5 mRNA occurs downstream of the increase in cytosolic calcium concentration caused by A beta. Moreover, DP5 specifically interacts with Bcl-xl during neuronal apoptosis following exposure to A beta, and its binding could impair the survival-promoting activities of Bcl-xl. Thus, the induction of DP5 mRNA and the interaction of DP5 and Bcl-xl could play significant roles in neuronal degeneration following exposure to A beta.
Highlights
Apoptosis, or programmed cell death, plays an important role in neuronal development and differentiation of the central nervous system and in the pathogenesis of a variety of neurodegenerative disorders such as Alzheimer’s disease
This gene has the following unique features: 1) the encoded protein has a BH3 domain, which is essential for interaction with Bcl-2 and Bcl-xl, and a transmembrane region at its C-terminal; 2) its expression shows marked induction with peak levels at 15 h after NGF withdrawal, concurrent with the time at which neurons are committed to die in the sympathetic culture model; and 3) overexpression of full-length DP5 in cultured neurons was sufficient to induce apoptosis
Some gene expression patterns induced by A  treatment were markedly similar to those of sympathetic neurons deprived of NGF, suggesting that a genetic cascade is necessary for neuronal death following exposure to A  to NGF-deprived neuronal death
Summary
Programmed cell death, plays an important role in neuronal development and differentiation of the central nervous system and in the pathogenesis of a variety of neurodegenerative disorders such as Alzheimer’s disease. We analyzed DP5 gene expression and the specific interaction of DP5 with Bcl-xl during neuronal death induced by amyloid- protein (A ).
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