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

Valya Ramakrishnan, Betty S. Pace

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27 Scopus citations


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
Issue number1
StatePublished - Jun 15 2011
Externally publishedYes

Bibliographical note

Funding Information:
We give special thanks to Dr. Li Liu in the Pace laboratory for cloning the pGγLuc2 reporter plasmid and TzuFang Lou for technical assistance with the two-phase liquid culture system. We greatly appreciate the assistance of Dr. Santosh D'Mello and Dr. Carole Mikoryak at the University of Texas at Dallas, with the fluorescence microscope studies. This work was supported by grant HL69234 from the National Heart Lung and Blood Institute to Dr. Betty Pace.


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


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