title: The MAPK ERK5, but not ERK1/2, inhibits the progression of monocytic phenotype to the functioning macrophage.
abstract: Intracellular signaling pathways present targets for pharmacological agents with potential for treatment of neoplastic diseases, with some disease remissions already recorded. However, cellular compensatory mechanisms usually negate the initial success. For instance, attempts to interrupt aberrant signaling downstream of the frequently mutated ras by inhibiting ERK1/2 has shown only limited usefulness for cancer therapy. Here, we examined how ERK5, that overlaps the functions of ERK1/2 in cell proliferation and survival, functions in a manner distinct from ERK1/2 in human AML cells induced to differentiate by 1,25D-dihydroxyvitamin D3 (1,25D). Using inhibitors of ERK1/2 and of MEK5/ERK5 at concentrations specific for each kinase in HL60 and U937 cells, we observed that selective inhibition of the kinase activity of ERK5, but not of ERK1/2, in the presence of 1,25D resulted in macrophage-like cell morphology and enhancement of phagocytic activity. Importantly, this was associated with increased expression of the macrophage colony stimulating factor receptor (M-CSFR), but was not seen when M-CSFR expression was knocked down. Interestingly, inhibition of ERK1/2 led to activation of ERK5 in these cells. Our results support the hypothesis that ERK5 negatively regulates the expression of M-CSFR, and thus has a restraining function on macrophage differentiation. The addition of pharmacological inhibitors of ERK5 may influence trials of differentiation therapy of AML.
authors.affiliation: Department of Pathology & Laboratory Medicine, Rutgers, NJ Medical School, 185 South Orange Ave, Newark, NJ 07103, USA.
authors.forename: Xuening
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Clinical Biochemistry & Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, PO Box 653, 84105 Beer-Sheva, Israel.
authors.forename: Stella
authors.initials: S
authors.lastname: Pesakhov
authors.affiliation: Department of Medicine, Rutgers, Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Harrison
authors.affiliation: Department of Clinical Biochemistry & Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, PO Box 653, 84105 Beer-Sheva, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Kafka
authors.affiliation: Department of Clinical Biochemistry & Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, PO Box 653, 84105 Beer-Sheva, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Danilenko
authors.affiliation: Department of Pathology & Laboratory Medicine, Rutgers, NJ Medical School, 185 South Orange Ave, Newark, NJ 07103, USA. Electronic address: studzins@njms.rutgers.edu.
authors.forename: George P
authors.initials: GP
authors.lastname: Studzinski
mesh_terms: D002454:Cell Differentiation; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D020298:U937 Cells
chemical_list: D047428:Protein Kinase Inhibitors; D016186:Receptor, Macrophage Colony-Stimulating Factor; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048054:Mitogen-Activated Protein Kinase 7
keywords: AML; ERK1/2; ERK5; M-CSFR; MAPK; Vitamin D