title: ERK5 pathway regulates transcription factors important for monocytic differentiation of human myeloid leukemia cells.
abstract: Mitogen-activated protein kinases (MAPKs) are important transducers of external signals for cell growth, survival, and other cellular responses including cell differentiation. Several MAPK cascades are known with the MEK1/2-ERK1/2, JNK, and p38MAPKs receiving most attention, but the role of MEK5-ERK5 in intracellular signaling deserves more scrutiny, as this pathway transmits signals that can complement ERK/2 signaling. We hypothesized that the ERK5 pathway plays a role in the control of monocytic differentiation, which is disturbed in myeloid leukemia. We therefore examined the cellular phenotype and key molecular events which occur when human myeloid leukemia cells, acute (AML) or chronic (CML), are forced to differentiate by vitamin D derivatives (VDDs). This study was performed using established cell lines HL60 and U937, and primary cultures of blasts from 10 patients with ML. We found that ERK5 and its direct downstream target transcription factor MEF2C are upregulated by 1,25D in parallel with monocytic differentiation. Further, inhibition of ERK5 activity by specific pharmacological agents BIX02189 and XMD8-92 alters the phenotype of these cells by reducing the abundance of the VDD-induced surface monocytic marker CD14, and concomitantly increasing surface expression of the general myeloid marker CD11b. Similar results were obtained when the expression of ERK5 was reduced by siRNA or short hairpin (sh) RNA. ERK5 inhibition resulted in an expected decrease in MEF2C activation. We also found that in AML cells the transcription factor C/EBPβ is positively regulated, while C/EBPα is negatively regulated by ERK5. These findings provide new understanding of dysregulated differentiation in human myeloid leukemia.
authors.affiliation: Department of Pathology and Laboratory Medicine, Rutgers Biomedical and Health Sciences, Newark, New Jersey.
authors.forename: Xuening
authors.initials: X
authors.lastname: Wang
authors.forename: Stella
authors.initials: S
authors.lastname: Pesakhov
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Harrison
authors.forename: Michael
authors.initials: M
authors.lastname: Danilenko
authors.forename: George P
authors.initials: GP
authors.lastname: Studzinski
mesh_terms: D000814:Aniline Compounds / Q000008:administration & dosage; D001570:Benzodiazepinones / Q000008:administration & dosage; D022782:CCAAT-Enhancer-Binding Protein-beta; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D064326:MEF2 Transcription Factors / Q000096:biosynthesis / Q000378:metabolism; D048054:Mitogen-Activated Protein Kinase 7 / Q000096:biosynthesis* / Q000235:genetics; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D020298:U937 Cells; D014807:Vitamin D / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D000814:Aniline Compounds; C533207:BIX 02189; D001570:Benzodiazepinones; D022782:CCAAT-Enhancer-Binding Protein-beta; D022762:CCAAT-Enhancer-Binding Proteins; C545012:CEBPB protein, human; D007211:Indoles; D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; D014157:Transcription Factors; C568790:XMD 8-92; D014807:Vitamin D; D048054:Mitogen-Activated Protein Kinase 7