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PLC-γ activation is required for PDGF-βR-mediated mitogenesis and monocytic differentiation of myeloid progenitor cells

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Abstract

To investigate the molecular mechanisms mediating hematopoietic cell differentiation and mitogenesis by activation of the platelet-derived growth factor β receptor (PDGF-βR), the wild type PDGF-βR (PDGF-βRWT) and tyrosine to phenylalanine mutants of the PDGF-βR, including F751, F966, F970, F1009, F1021 and F1009/F1021 were overexpressed in FDC-P2 myeloid progenitor cells by retroviral-mediated gene transfer. Stimulation of PDGF-βRWT and F966, F970 and F1009 infectants with PDGF-BB led to the increased expression of monocytic differentiation markers. In contrast, activation of PDGF-βR in the parental line or the F1021 or F1009/F1021 mutant infectants failed to induce monocytic differentiation. PDGF-BB stimulation of PDGF-βRWT, F751, F966, F970 and F1009 infectants led to pronounced DNA synthesis, whereas F1021 and F1009/F1021 infectants did not reveal any increase in mitogenesis when compared to that of the FDC-P2 line. While PDGF stimulation of FDC-P2 cells overexpressing PDGF-βRWT led to a pronounced increase in inositol phosphate formation due to phospholipase C-γ (PLC-γ) activation, PDGF-BB induced phosphoinositol hydrolysis was completely abolished in the F1021 and F1009/F1021 infectants. GF 109203X, a specific inhibitor of protein kinase C (PKC) activation, fully blocked PDGF-βR-mediated monocytic differentiation and mitogenesis. Taken together, these results suggest that stimulation of the PDGF-βR signaling pathway can mediate monocytic differentiation when PDGF-βR is expressed at sufficient levels and that activation of PLC-γ and PKC plays a pivotal role in PDGF-βR-mediated differentiation and mitogenesis in FDC-P2 cell system.

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Alimandi, M., Heidaran, M., Gutkind, J. et al. PLC-γ activation is required for PDGF-βR-mediated mitogenesis and monocytic differentiation of myeloid progenitor cells. Oncogene 15, 585–593 (1997). https://doi.org/10.1038/sj.onc.1201221

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  • DOI: https://doi.org/10.1038/sj.onc.1201221

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