Regulation of γ-globin gene expression involves signaling through the p38 MAPK/CREB1 pathway

Valya Ramakrishnan, Betty S. Pace

Research output: Contribution to journalArticle

23 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)12-22
Number of pages11
JournalBlood Cells, Molecules, and Diseases
Volume47
Issue number1
DOIs
StatePublished - Jun 15 2011

Keywords

  • CREB1
  • Globin gene regulation
  • P38 MAPK
  • γ-globin

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Hematology
  • Cell Biology

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