A role for nuclear phospholipase Cbeta 1 in cell cycle control.
Phosphoinositide signaling resides in the nucleus, and among the enzymes of the cycle, phospholipase C (PLC) appears as the key element both in Saccharomyces cerevisiae and in mammalian cells. The yeast PLC pathway produces multiple inositol polyphosphates that modulate distinct nuclear processes. The mammalian PLCbeta(1), which localizes in the nucleus, is activated in insulin-like growth factor 1-mediated mitogenesis and undergoes down-regulation during murine erythroleukemia differentiation. PLCbeta(1) exists as two polypeptides of 150 and 140 kDa generated from a single gene by alternative RNA splicing, both of them containing in the COOH-terminal tail a cluster of lysine residues responsible for nuclear localization. These clues prompted us to try to establish the critical nuclear target(s) of PLCbeta(1) subtypes in the control of cell cycle progression. The results reveal that the two subtypes of PLCbeta(1) that localize in the nucleus induce cell cycle progression in Friend erythroleukemia cells. In fact when they are overexpressed in the nucleus, cyclin D3, along with its kinase (cdk4) but not cyclin E is overexpressed even though cells are serum-starved. As a consequence of this enforced expression, retinoblastoma protein is phosphorylated and E2F-1 transcription factor is activated as well. On the whole the results reveal a direct effect of nuclear PLCbeta(1) signaling in G(1) progression by means of a specific target, i.e. cyclin D3/cdk4.
Department of Anatomical Sciences, Cellular Signalling Laboratory, University of Bologna, Via Irnerio 48, I-40126 Bologna, Italy.
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Matteucci
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Manzoli
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Billi
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Aluigi
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Peruzzi
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Vitale
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Castorina
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D000818:Animals; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism*; D016895:Culture Media, Serum-Free; D056743:Cyclin D3; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D016193:G1 Phase / Q000502:physiology*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D019913:Nuclear Localization Signals / Q000235:genetics; D054799:Phospholipase C beta; D010766:Phosphorylation; D011485:Protein Binding; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D056465:Retinoblastoma-Binding Protein 1; D015398:Signal Transduction; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism*
C533431:Arid4a protein, mouse; D002352:Carrier Proteins; C534697:Ccnd3 protein, mouse; D018797:Cell Cycle Proteins; D016895:Culture Media, Serum-Free; D056743:Cyclin D3; D019927:Cyclin E; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D007527:Isoenzymes; D019913:Nuclear Localization Signals; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D010738:Type C Phospholipases; D054799:Phospholipase C beta