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Inositide-Dependent Phospholipase C Signaling Mimics Insulin in Skeletal Muscle Differentiation by Affecting Specific Regions of the Cyclin D3 Promoter

Cellular Signalling Laboratory (I.F., G.R., R.F., G.C.G., M.Y.F., A.M.M., L.C.), Department of Human Anatomical Science, University of Bologna, 40126 Bologna, Italy; Laboratory of Cell Biology and Electron Microscopy (A.B.), Istituti Ortopedici Rizzoli, 40136 Bologna, Italy; Department of Pathology (R.S.G.), University of Cambridge, Cambridge CB2 1QP, United Kingdom; and Departments of Biochemistry and Medicine and Whitaker Cardiovascular Institute (K.R.), Boston University School of Medicine, Boston, Massachusetts 02118

Address all correspondence and requests for reprints to: Dr. Lucio Cocco, Cellular Signalling Laboratory, Department of Human Anatomical Sciences, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy. E-mail: lcocco{at}biocfarm.unibo.it.

Our main goal in this study was to investigate the role of phospholipase C (PLC) ß₁ and PLC₁ in skeletal muscle differentiation and the existence of potential downstream targets of their signaling activity. To examine whether PLC signaling can modulate the expression of cyclin D3, a target of PLCß₁ in erythroleukemia cells, we transfected C2C12 cells with expression vectors containing PLCß₁ or PLC₁ cDNA and with small interfering RNAs from regions of the PLCß₁ or PLC₁ gene and followed myogenic differentiation in this well-established cell system. Intriguingly, overexpressed PLCß₁ and PLC₁ were able to mimic insulin induction of both cyclin D3 and muscle differentiation. By knocking down PLCß₁ or PLC₁ expression, C2C12 cells almost completely lost the increase in cyclin D3, and the differentiation program was down-regulated. To explore the induction of the cyclin D3 gene promoter during this process, we used a series of 5'-deletions of the 1.68-kb promoter linked to a reporter gene and noted a 5-fold augmentation of promoter activity upon insulin stimulation. These constructs were also cotransfected with PLCß₁ or PLC₁ cDNAs and small interfering RNAs, respectively. Our data indicate that PLCß₁ or PLC₁ signaling is capable of acting like insulin in regard to both the myogenic differentiation program and cyclin D3 up-regulation. Taken together, this is the first study that hints at cyclin D3 as a target of PLCß₁ and PLC₁ during myogenic differentiation in vitro and implies that up-regulation of these enzymes is sufficient to mimic the actions of insulin in this process.

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