Extracellular signal-regulated kinase induces the megakaryocyte GPIIb/CD41 gene through MafB/Kreisler.
Extracellular signal-regulated kinase (ERK) facilitates cell cycle progression in most mammalian cells, but in certain cell types prolonged signaling through this pathway promotes differentiation and lineage-specific gene expression through mechanisms that are poorly understood. Here, we characterize the transcriptional regulation of platelet GPIIb integrin (CD41) by ERK during megakaryocyte differentiation. ERK-dependent transactivation involves the proximal promoter of GPIIb within 114 bp upstream of the transcriptional start site. GATA, Ets, and Sp1 consensus sequences within this region are each necessary and function combinatorially in ERK-activated transcription. MafB/Kreisler is induced in response to ERK and synergizes with GATA and Ets to enhance transcription from the proximal promoter. The requirement for MafB in promoter regulation is demonstrated by inhibition of transactivation following dominant-negative or antisense suppression of MafB function. Thus, ERK promotes megakaryocyte differentiation by coordinate regulation of nuclear factors that synergize in GPIIb promoter regulation. These results establish a novel role for MafB as a regulator of ERK-induced gene expression.
Sevinsky
Joel R
JR
Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado 80309, USA.
Whalen
Anne M
AM
Ahn
Natalie G
NG
D030161:Avian Proteins; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D050981:Erythroid-Specific DNA-Binding Factors; D005786:Gene Expression Regulation; D006801:Humans; D020014:K562 Cells; D051258:MafB Transcription Factor; D008533:Megakaryocytes / Q000276:immunology* / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D040201:Platelet Membrane Glycoprotein IIb / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D030161:Avian Proteins; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; C490407:MAFB protein, human; D051258:MafB Transcription Factor; D015513:Oncogene Proteins; D040201:Platelet Membrane Glycoprotein IIb; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D011994:Recombinant Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D004247:DNA; D020928:Mitogen-Activated Protein Kinases