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Nuclear but not Cytoplasmic Phospholipase C ß₁ Inhibits Differentiation of Erythroleukemia Cells¹

Institute of Cytomorphology, Consiglio Nazionale delle Ricerche and Cell Biology Laboratory, Istituto Rizzoli, I-40136 Bologna, Italy [A. M., A. B.]; Cellular Signalling Laboratory, Institute of Anatomy, University of Bologna, I-40126 Bologna, Italy [I. F., L. M., A. M. B., D. P., L. C.]; University of Auckland, Faculty of Medicine, Auckland, New Zealand [R. S. G.]; and Laboratory of Cell Signaling, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland 20892 [S-G. R.]

A body of evidence has shown the existence of a nuclear phosphoinositide cycle in different cell types. The cycle is endowed with kinases as well as phosphatases and phospholipase C (PLC). Among the PLC isozymes, the ß family is characterized by a long COOH-terminal tail that contains a cluster of lysine residues responsible for nuclear localization. Indeed, PLCß₁ is the major isoform that has been detected in the nucleus of several cells. This isoform is activated by insulin-like growth factor I, and when this isoform is lacking, as a result of gene ablation, the onset of DNA synthesis induced by this hormone is abolished. On the contrary, PLCß₁ is down-regulated during the erythroid differentiation of Friend erythroleukemia cells. A key question is how PLCß₁ signaling at the nucleus fits into the erythroid differentiation program of Friend erythroleukemia cells, and whether PLCß₁ signaling activity is directly responsible for the maintenance of the undifferentiated state of erythroleukemia cells. Here we present evidence that nuclear PLCß₁ but not the isoform located at the plasma membrane is directly involved in maintaining the undifferentiated state of Friend erythroleukemia cells. Indeed, when wild-type PLCß₁ is overexpressed in these cells, differentiation in response to DMSO is inhibited in that the expression of ß-globin is almost completely abolished, whereas when a mutant lacking the ability to localize to the nucleus is expressed, the cells differentiate, and the expression of ß-globin is the same as in wild-type cells.

¹ Supported by the Italian Association for Cancer Research, Funds for Selected Research Topics of Bologna University, and the Italian Consiglio Nazionale delle Ricerche Finalized Project Biotechnology.

² A. M. and I. F. contributed equally to this work.

³ To whom requests for reprints should be addressed, at Cellular Signaling Laboratory, Institute of Anatomy, University of Bologna, Via Irnerio, 48, I-40126 Bologna, Italy. Phone: 39-0-51-244467; Fax: 39-0-51-251735; E-mail: lcocco@biocfarm.unibo.it.

Received 8/28/98. Accepted 9/29/98.

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