title: Regulation of γ-globin gene expression involves signaling through the p38 MAPK/CREB1 pathway.
abstract: In response to sodium butyrate and trichostatin A treatment in erythroid cells, p38 mitogen activated protein kinase (MAPK) mediates fetal hemoglobin (HbF) induction by activating cAMP response element binding protein 1 (CREB1). To expand on this observation, we completed studies to determine the role of p38 MAPK in steady-state γ-globin regulation. We propose that p38 signaling regulates Gγ-globin transcription during erythroid maturation through its downstream effector CREB1 which binds the Gγ-globin cAMP response element (G-CRE). We demonstrated that a loss of p38 or CREB1 function by siRNA knockdown resulted in target gene silencing. Moreover, gain of p38 or CREB1 function augments γ-globin transcription. These regulatory effects were conserved under physiological conditions tested in primary erythroid cells. When the G-CRE was mutated in a stable chromatin environment Gγ-globin promoter activity was nearly abolished. Furthermore, introduction of mutations in the G-CRE abolished Gγ-globin activation via p38 MAPK/CREB1 signaling. Chromatin immunoprecipitation assays (ChIP) demonstrated that CREB1 and its binding partner CREB binding protein (CBP) co-localize at the G-CRE region. These data support the role of p38 MAPK/CREB1 signaling in Gγ-globin gene transcription under steady-state conditions.
authors.affiliation: Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, TX 75080, USA.
authors.forename: Valya
authors.initials: V
authors.lastname: Ramakrishnan
authors.forename: Betty S
authors.initials: BS
authors.lastname: Pace
mesh_terms: D001483:Base Sequence; D050882:CREB-Binding Protein / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D015672:Erythroid Precursor Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D023061:Gene Order; D006801:Humans; D020014:K562 Cells; D011485:Protein Binding / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics; D055545:gamma-Globins / Q000235:genetics* / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D055545:gamma-Globins; D050882:CREB-Binding Protein; D048051:p38 Mitogen-Activated Protein Kinases