title: Nuclear ERK5 inhibits progression of leukemic monocytes to macrophages by regulating the transcription factor PU.1 and heat shock protein HSP70.
abstract: Differentiation therapy can supplement the therapy of APL, but other subtypes of AML are treated principally with cytotoxic agents, with few lasting remissions. While the induction of monocyte followed by macrophage differentiation by vitamin D derivatives (VDDs) is dramatic in cultured AML cells of all subtypes, attempts to translate this to the clinic have not been effective. Thus, better understanding of the mechanisms underlying VDD-induced differentiation may improve this approach. The key events in this form of differentiation include increased expression of CD11b, and the transcription factor PU.1 is known to be a part of this process. We show here that in the transition of monocytes to macrophages induced by a VDD, ERK5, a member of the MAPK family of signaling molecules, prevents PU.1 expression. However, upon ERK5 inhibition PU.1 protein is stabilized by HSP70.Thus, ERK5 may be a target for manipulation of the immunoregulatory actions of macrophages in cancer.
authors.affiliation: a Department of Pathology and Laboratory Medicine , New Jersey Medical School, Rutgers University , Newark , NJ , USA.
authors.forename: Ruifang
authors.initials: R
authors.lastname: Zheng
authors.affiliation: a Department of Pathology and Laboratory Medicine , New Jersey Medical School, Rutgers University , Newark , NJ , USA.
authors.forename: George P
authors.initials: GP
authors.lastname: Studzinski
mesh_terms: D015415:Biomarkers; D039481:CD11b Antigen / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D015415:Biomarkers; D039481:CD11b Antigen; D018840:HSP70 Heat-Shock Proteins; D048054:Mitogen-Activated Protein Kinase 7; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1
keywords: 1; 25-dyhydroxyvitamin D3; AML; ERK5; differentiation; heat shock protein