title: PI-PLCβ1b affects Akt activation, cyclin E expression, and caspase cleavage, promoting cell survival in pro-B-lymphoblastic cells exposed to oxidative stress.
abstract: The phosphoinositide-dependent signal transduction pathway has been implicated in the control of a variety of biologic processes, such as the regulation of cellular metabolism and homeostasis, cell proliferation and differentiation, and apoptosis. One of the key players in the regulation of inositol lipid signaling is the phospholipase Cβ1 (PI-PLCβ1), that hydrolyzes phosphatidylinositol 4,5-bisphosphate [PtIns(4,5)P2], giving rise to the second messengers inositol triphosphate and diacylglicerol. PI-PLCβ1 has been associated with the regulation of several cellular functions, some of which have not yet been fully understood. In particular, it has been reported that PI-PLCβ1 protects murine fibroblasts from oxidative stress-induced cell death. The mediators of oxidative stress, reactive oxygen species (ROS), have been shown to regulate major epigenetic processes, causing the silencing of tumor suppressors and enhancing the proliferation of leukemic cells under oxidative stress. Investigation of the interplay between ROS, PI-PLCβ1, and their signaling mediators in leukemia might therefore reveal innovative targets of pharmacological therapy in the treatment for leukemia. In this work, we demonstrate that in pro-B-lymphoblastic cells (Ba/F3), treated with H2O2, PI-PLCβ1b conferred resistance to cell death, promoting cell cycle progression and cell proliferation and influencing the expression of cyclin A and E. Interestingly, we found that, expression of PI-PLCβ1b affects the activity of caspase-3, caspase-7, and of several protein kinases induced by oxidative stress. In particular, PI-PLCβ1b expression completely abolished the phosphorylation of Erk1/2 MAP kinases, down-regulated phosphatase and tensin homolog (PTEN), and up-regulated the phosphorylation of Akt, thereby sustaining cellular proliferation.
authors.affiliation: *Cell Signaling Laboratory, Department of Biomedical Sciences, University of Bologna, Bologna, Italy; Struttura Complessa Laboratory of Musculoskeletal Cell Biology, Rizzoli Orthopedic Institute, Bologna, Italy; Institute of Molecular Genetics, National Research Council of Italy, Bologna, Italy; and RAMSES Laboratory, Rizzoli Orthopedic Institute, Bologna, Italy manuela.piazzi3@unibo.it manuela.piazzi@gmail.com.
authors.forename: Manuela
authors.initials: M
authors.lastname: Piazzi
authors.affiliation: *Cell Signaling Laboratory, Department of Biomedical Sciences, University of Bologna, Bologna, Italy; Struttura Complessa Laboratory of Musculoskeletal Cell Biology, Rizzoli Orthopedic Institute, Bologna, Italy; Institute of Molecular Genetics, National Research Council of Italy, Bologna, Italy; and RAMSES Laboratory, Rizzoli Orthopedic Institute, Bologna, Italy.
authors.forename: William L
authors.initials: WL
authors.lastname: Blalock
authors.affiliation: *Cell Signaling Laboratory, Department of Biomedical Sciences, University of Bologna, Bologna, Italy; Struttura Complessa Laboratory of Musculoskeletal Cell Biology, Rizzoli Orthopedic Institute, Bologna, Italy; Institute of Molecular Genetics, National Research Council of Italy, Bologna, Italy; and RAMSES Laboratory, Rizzoli Orthopedic Institute, Bologna, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bavelloni
authors.affiliation: *Cell Signaling Laboratory, Department of Biomedical Sciences, University of Bologna, Bologna, Italy; Struttura Complessa Laboratory of Musculoskeletal Cell Biology, Rizzoli Orthopedic Institute, Bologna, Italy; Institute of Molecular Genetics, National Research Council of Italy, Bologna, Italy; and RAMSES Laboratory, Rizzoli Orthopedic Institute, Bologna, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Faenza
authors.affiliation: *Cell Signaling Laboratory, Department of Biomedical Sciences, University of Bologna, Bologna, Italy; Struttura Complessa Laboratory of Musculoskeletal Cell Biology, Rizzoli Orthopedic Institute, Bologna, Italy; Institute of Molecular Genetics, National Research Council of Italy, Bologna, Italy; and RAMSES Laboratory, Rizzoli Orthopedic Institute, Bologna, Italy.
authors.forename: Mirco
authors.initials: M
authors.lastname: Raffini
authors.affiliation: *Cell Signaling Laboratory, Department of Biomedical Sciences, University of Bologna, Bologna, Italy; Struttura Complessa Laboratory of Musculoskeletal Cell Biology, Rizzoli Orthopedic Institute, Bologna, Italy; Institute of Molecular Genetics, National Research Council of Italy, Bologna, Italy; and RAMSES Laboratory, Rizzoli Orthopedic Institute, Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Tagliavini
authors.affiliation: *Cell Signaling Laboratory, Department of Biomedical Sciences, University of Bologna, Bologna, Italy; Struttura Complessa Laboratory of Musculoskeletal Cell Biology, Rizzoli Orthopedic Institute, Bologna, Italy; Institute of Molecular Genetics, National Research Council of Italy, Bologna, Italy; and RAMSES Laboratory, Rizzoli Orthopedic Institute, Bologna, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Manzoli
authors.affiliation: *Cell Signaling Laboratory, Department of Biomedical Sciences, University of Bologna, Bologna, Italy; Struttura Complessa Laboratory of Musculoskeletal Cell Biology, Rizzoli Orthopedic Institute, Bologna, Italy; Institute of Molecular Genetics, National Research Council of Italy, Bologna, Italy; and RAMSES Laboratory, Rizzoli Orthopedic Institute, Bologna, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Cocco
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival; D019925:Cyclin A / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000633:toxicity; D007377:Interleukin-3 / Q000378:metabolism; D051379:Mice; D018384:Oxidative Stress; D054799:Phospholipase C beta / Q000378:metabolism*; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019925:Cyclin A; D019927:Cyclin E; D006575:Heterocyclic Compounds, 3-Ring; D007377:Interleukin-3; C548887:MK 2206; D006861:Hydrogen Peroxide; D051057:Proto-Oncogene Proteins c-akt; D054799:Phospholipase C beta; C518034:Plcb1 protein, mouse; C505409:Casp3 protein, mouse; C505524:Casp7 protein, mouse; D053148:Caspase 3; D053179:Caspase 7
keywords: MAPK; PKR; ROS; effector caspases; leukemia