title: Feedback regulation mediated by Bcl-2 and DARPP-32 regulates inositol 1,4,5-trisphosphate receptor phosphorylation and promotes cell survival.
abstract: Bcl-2 interacts with the inositol 1,4,5-trisphosphate receptor (InsP3R) and thus prevents InsP3-induced Ca(2+) elevation that induces apoptosis. Here we report that Bcl-2 binds dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), a protein kinase A (PKA)-activated and calcineurin (CaN)-deactivated inhibitor of protein phosphatase 1 (PP1). Bcl-2 docks DARPP-32 and CaN in a complex on the InsP3R, creating a negative feedback loop that prevents exaggerated Ca(2+) release by decreasing PKA-mediated InsP3R phosphorylation. T-cell activation increases PKA activity, phosphorylating both the InsP3R and DARPP-32. Phosphorylated DARPP-32 inhibits PP1, enhancing InsP3R phosphorylation and Ca(2+) release. Elevated Ca(2+) activates CaN, which dephosphorylates DARPP-32 to dampen Ca(2+) release by eliminating PP1 inhibition to enable it to dephosphorylate the InsP3R. Knocking down either Bcl-2 or DARPP-32 abrogates this feedback mechanism, resulting in increased Ca(2+) elevation and apoptosis. This feedback mechanism appears to be exploited by high levels of Bcl-2 in chronic lymphocytic leukemia cells, repressing B-cell receptor-induced Ca(2+) elevation and apoptosis.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, OH 44106.
authors.forename: Ming-Jin
authors.initials: MJ
authors.lastname: Chang
authors.forename: Fei
authors.initials: F
authors.lastname: Zhong
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Lavik
authors.forename: Jan B
authors.initials: JB
authors.lastname: Parys
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Berridge
authors.forename: Clark W
authors.initials: CW
authors.lastname: Distelhorst
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D019169:Jurkat Cells; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction
chemical_list: D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D053496:Inositol 1,4,5-Trisphosphate Receptors; C497928:PPP1R1B protein, human; C497929:Ppp1r1b protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D017868:Cyclic AMP-Dependent Protein Kinases; D019703:Calcineurin; D002118:Calcium
keywords: calcium; cancer; lymphocyte; signal transduction; signaling