{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,26]],"date-time":"2025-10-26T14:42:51Z","timestamp":1761489771482,"version":"3.37.3"},"reference-count":24,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2015,9,2]],"date-time":"2015-09-02T00:00:00Z","timestamp":1441152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100004099","name":"Ligue Nationale Contre le Cancer","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004099","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004097","name":"Fondation ARC pour la recherche sur le Cancer.","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004097","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>M-CSF and G-CSF are instructive cytokines that specifically induce differentiation of bipotent myeloid progenitors into macrophages and granulocytes, respectively. Through morphology and colony assay studies, flow cytometry analysis of specific markers, and expression of myeloid transcription factors, we show here that the Eger\/Fms cell line is composed of cells whose differentiation fate is instructed by M-CSF and G-CSF, thus representing a good in vitro model of myeloid bipotent progenitors. Consistent with the essential role of ERK1\/2 during macrophage differentiation and defects of macrophagic differentiation in native ERK1\u2212\/\u2212 progenitors, ERK signaling is strongly activated in Eger\/Fms cells upon M-CSF-induced macrophagic differentiation but only to a very small extent during G-CSF-induced granulocytic differentiation. Previous in vivo studies indicated a key role of Fli-1 in myeloid differentiation and demonstrated its weak expression during macrophagic differentiation with a strong expression during granulocytic differentiation. Here, we demonstrated that this effect could be mediated by a differential regulation of protein kinase C\u03b4 (PKCd) on Fli-1 expression in response to M-CSF and G-CSF. With the use of knockdown of PKCd by small interfering RNA, we demonstrated that M-CSF activates PKCd, which in turn, inhibits Fli-1 expression and granulocytic differentiation. Finally, we studied the connection between ERK and PKCd and showed that in the presence of the MEK inhibitor U0126, PKCd expression is decreased, and Fli-1 expression is increased in response to M-CSF. Altogether, we demonstrated that in bipotent myeloid cells, M-CSF promotes macrophagic over granulocytic differentiation by inducing ERK activation but also PKCd expression, which in turn, down-regulates Fli-1 expression and prevents granulocytic differentiation.<\/jats:p>","DOI":"10.1189\/jlb.2a1214-619r","type":"journal-article","created":{"date-parts":[[2015,9,3]],"date-time":"2015-09-03T01:43:50Z","timestamp":1441244630000},"page":"311-319","source":"Crossref","is-referenced-by-count":4,"title":["Instructive role of M-CSF on commitment of bipotent myeloid cells involves ERK-dependent positive and negative signaling"],"prefix":"10.1093","volume":"99","author":[{"given":"Sylvain","family":"Carras","sequence":"first","affiliation":[{"name":"Centre de G\u00e9n\u00e9tique et de Physiologie Mol\u00e9culaire et Cellulaire, Centre National de la Recherche Scientifique, Unit\u00e9s Mixtes de Recherche 5534, Universit\u00e9 de Lyon , Villeurbanne Cedex , France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandre","family":"Valayer","sequence":"additional","affiliation":[{"name":"Centre de G\u00e9n\u00e9tique et de Physiologie Mol\u00e9culaire et Cellulaire, Centre National de la Recherche Scientifique, Unit\u00e9s Mixtes de Recherche 5534, Universit\u00e9 de Lyon , Villeurbanne Cedex , France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudine","family":"Moratal","sequence":"additional","affiliation":[{"name":"Centre de G\u00e9n\u00e9tique et de Physiologie Mol\u00e9culaire et Cellulaire, Centre National de la Recherche Scientifique, Unit\u00e9s Mixtes de Recherche 5534, Universit\u00e9 de Lyon , Villeurbanne Cedex , France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mich\u00e8le","family":"Weiss-Gayet","sequence":"additional","affiliation":[{"name":"Centre de G\u00e9n\u00e9tique et de Physiologie Mol\u00e9culaire et Cellulaire, Centre National de la Recherche Scientifique, Unit\u00e9s Mixtes de Recherche 5534, Universit\u00e9 de Lyon , Villeurbanne Cedex , France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gilles","family":"Pages","sequence":"additional","affiliation":[{"name":"Centre de G\u00e9n\u00e9tique et de Physiologie Mol\u00e9culaire et Cellulaire, Centre National de la Recherche Scientifique, Unit\u00e9s Mixtes de Recherche 5534, Universit\u00e9 de Lyon , Villeurbanne Cedex , France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francois","family":"Morl\u00e9","sequence":"additional","affiliation":[{"name":"Centre de G\u00e9n\u00e9tique et de Physiologie Mol\u00e9culaire et Cellulaire, Centre National de la Recherche Scientifique, Unit\u00e9s Mixtes de Recherche 5534, Universit\u00e9 de Lyon , Villeurbanne Cedex , France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guy","family":"Mouchiroud","sequence":"additional","affiliation":[{"name":"Centre de G\u00e9n\u00e9tique et de Physiologie Mol\u00e9culaire et Cellulaire, Centre National de la Recherche Scientifique, Unit\u00e9s Mixtes de Recherche 5534, Universit\u00e9 de Lyon , Villeurbanne Cedex , France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"St\u00e9phanie","family":"Gobert","sequence":"additional","affiliation":[{"name":"Centre de G\u00e9n\u00e9tique et de Physiologie Mol\u00e9culaire et Cellulaire, Centre National de la Recherche Scientifique, Unit\u00e9s Mixtes de Recherche 5534, Universit\u00e9 de Lyon , Villeurbanne Cedex , France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2015,9,2]]},"reference":[{"key":"2023013012482491400_B1","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/35030112","article-title":"Cell-fate conversion of lymphoid-committed progenitors by instructive actions of cytokines","volume":"407","author":"Kondo","year":"2000","journal-title":"Nature"},{"key":"2023013012482491400_B2","doi-asserted-by":"crossref","first-page":"11872","DOI":"10.1073\/pnas.172384399","article-title":"Prospective isolation of human clonogenic common myeloid progenitors","volume":"99","author":"Manz","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023013012482491400_B3","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1038\/sj.leu.2404690","article-title":"Signal transduction pathways that contribute to myeloid differentiation","volume":"21","author":"Miranda","year":"2007","journal-title":"Leukemia"},{"key":"2023013012482491400_B4","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1126\/science.1171461","article-title":"Hematopoietic cytokines can instruct lineage choice","volume":"325","author":"Rieger","year":"2009","journal-title":"Science"},{"key":"2023013012482491400_B5","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1016\/j.cellsig.2005.02.002","article-title":"M-CSF stimulated differentiation requires persistent MEK activity and MAPK phosphorylation independent of Grb2-Sos association and phosphatidylinositol 3-kinase activity","volume":"17","author":"Gobert Gosse","year":"2005","journal-title":"Cell. Signal."},{"key":"2023013012482491400_B6","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1189\/jlb.0309151","article-title":"Macrophage differentiation of myeloid progenitor cells in response to M-CSF is regulated by the dual-specificity phosphatase DUSP5","volume":"87","author":"Grasset","year":"2010","journal-title":"J. Leukoc. Biol."},{"key":"2023013012482491400_B7","doi-asserted-by":"crossref","first-page":"2172","DOI":"10.1182\/blood-2008-11-191536","article-title":"M-CSF elevates c-Fos and phospho-C\/EBPalpha(S21) via ERK whereas G-CSF stimulates SHP2 phosphorylation in marrow progenitors to contribute to myeloid lineage specification","volume":"114","author":"Jack","year":"2009","journal-title":"Blood"},{"key":"2023013012482491400_B8","doi-asserted-by":"crossref","first-page":"3290","DOI":"10.1038\/sj.onc.1203627","article-title":"STAT3-mediated differentiation and survival and of myeloid cells in response to granulocyte colony-stimulating factor: role for the cyclin-dependent kinase inhibitor p27(Kip1)","volume":"19","author":"De Koning","year":"2000","journal-title":"Oncogene"},{"key":"2023013012482491400_B9","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/sj.onc.1209777","article-title":"E2a\/Pbx1 oncogene inhibits terminal differentiation but not myeloid potential of pro-T cells","volume":"26","author":"Bourette","year":"2007","journal-title":"Oncogene"},{"key":"2023013012482491400_B10","doi-asserted-by":"crossref","first-page":"4795","DOI":"10.1182\/blood-2010-02-270405","article-title":"Inducible Fli-1 gene deletion in adult mice modifies several myeloid lineage commitment decisions and accelerates proliferation arrest and terminal erythrocytic differentiation","volume":"116","author":"Starck","year":"2010","journal-title":"Blood"},{"key":"2023013012482491400_B11","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.1128\/MCB.01320-08","article-title":"Phosphorylation of Fli1 at threonine 312 by protein kinase C delta promotes its interaction with p300\/CREB-binding protein-associated factor and subsequent acetylation in response to transforming growth factor beta","volume":"29","author":"Asano","year":"2009","journal-title":"Mol. Cell. Biol."},{"key":"2023013012482491400_B12","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1189\/jlb.0702359","article-title":"M-CSF induced differentiation of myeloid precursor cells involves activation of PKC-delta and expression of Pkare","volume":"73","author":"Junttila","year":"2003","journal-title":"J. Leukoc. Biol."},{"key":"2023013012482491400_B13","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/sj.leu.2404986","article-title":"Src-family kinases play an essential role in differentiation signaling downstream of macrophage colony-stimulating factor receptors mediating persistent phosphorylation of phospholipase C-gamma2 and MAP kinases ERK1 and ERK2","volume":"22","author":"Bourgin-Hierle","year":"2008","journal-title":"Leukemia"},{"key":"2023013012482491400_B14","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1016\/j.cell.2006.06.052","article-title":"Multilineage transcriptional priming and determination of alternate hematopoietic cell fates","volume":"126","author":"Laslo","year":"2006","journal-title":"Cell"},{"key":"2023013012482491400_B15","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1038\/leu.2010.195","article-title":"Gfi1 and Gfi1b: key regulators of hematopoiesis","volume":"24","author":"Van der Meer","year":"2010","journal-title":"Leukemia"},{"key":"2023013012482491400_B16","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/S1074-7613(02)00501-0","article-title":"Intrinsic requirement for zinc finger transcription factor Gfi-1 in neutrophil differentiation","volume":"18","author":"Hock","year":"2003","journal-title":"Immunity"},{"key":"2023013012482491400_B17","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1182\/blood.V97.5.1298","article-title":"Early growth response gene 1 stimulates development of hematopoietic progenitor cells along the macrophage lineage at the expense of the granulocyte and erythroid lineages","volume":"97","author":"Krishnaraju","year":"2001","journal-title":"Blood"},{"key":"2023013012482491400_B18","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S0014-5793(00)01906-2","article-title":"Expression of Mona (monocytic adapter) in myeloid progenitor cells results in increased and prolonged MAP kinase activation upon macrophage colony-stimulating factor stimulation","volume":"480","author":"Bourgin","year":"2000","journal-title":"FEBS Lett."},{"key":"2023013012482491400_B19","doi-asserted-by":"crossref","first-page":"e30788","DOI":"10.1371\/journal.pone.0030788","article-title":"ERK1 regulates the hematopoietic stem cell niches","volume":"7","author":"Saulnier","year":"2012","journal-title":"PLoS One"},{"key":"2023013012482491400_B20","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1203\/01.PDR.0000147729.55592.2C","article-title":"G-CSF induces stabilization of ETS protein Fli-1 during myeloid cell development","volume":"57","author":"Mora-Garcia","year":"2005","journal-title":"Pediatr. Res."},{"key":"2023013012482491400_B21","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1038\/sj.leu.2401822","article-title":"The SH2 domain-containing protein tyrosine phosphatase SHP-1 is induced by granulocyte colony-stimulating factor (G-CSF) and modulates signaling from the G-CSF receptor","volume":"14","author":"Ward","year":"2000","journal-title":"Leukemia"},{"key":"2023013012482491400_B22","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1002\/jcb.24653","article-title":"PLC\u03b32 and PKC are important to myeloid lineage commitment triggered by M-SCF and G-CSF","volume":"115","author":"Barbosa","year":"2014","journal-title":"J. Cell. Biochem."},{"key":"2023013012482491400_B23","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1111\/j.1365-2133.2012.11055.x","article-title":"Constitutive activation of c-Abl\/protein kinase C-\u03b4\/Fli1 pathway in dermal fibroblasts derived from patients with localized scleroderma","volume":"167","author":"Noda","year":"2012","journal-title":"Br. J. Dermatol."},{"key":"2023013012482491400_B24","doi-asserted-by":"crossref","first-page":"G317","DOI":"10.1152\/ajpgi.00363.2011","article-title":"PKC\u03b4-dependent activation of ERK1\/2 leads to upregulation of the human NHE2 transcriptional activity in intestinal epithelial cell line C2BBe1","volume":"302","author":"Muthusamy","year":"2012","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."}],"container-title":["Journal of Leukocyte Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1189%2Fjlb.2A1214-619R","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jleukbio\/article-pdf\/99\/2\/311\/48176304\/jlb0311.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jleukbio\/article-pdf\/99\/2\/311\/48176304\/jlb0311.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,27]],"date-time":"2023-02-27T13:31:40Z","timestamp":1677504700000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jleukbio\/article\/99\/2\/311\/6936068"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,9,2]]},"references-count":24,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2015,9,2]]},"published-print":{"date-parts":[[2016,2,1]]}},"URL":"https:\/\/doi.org\/10.1189\/jlb.2a1214-619r","relation":{},"ISSN":["0741-5400","1938-3673"],"issn-type":[{"type":"print","value":"0741-5400"},{"type":"electronic","value":"1938-3673"}],"subject":[],"published-other":{"date-parts":[[2016,2]]},"published":{"date-parts":[[2015,9,2]]}}}