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Prepublished online as a Blood First Edition Paper on June 28, 2002; DOI 10.1182/blood-2001-12-0374.
Submitted January 2, 2002
Accepted June 4, 2002
IL-3 induced enhancement of RA receptor activity is mediated through Stat5, which physically associates with retinoic acid receptors in an IL-3 dependent manner
Jutong Si and Steven J Collins*
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
* Corresponding author; email: scollins{at}fhcrc.org.
The regulation of hematopoiesis involves the interaction of specific hematopoietic cytokines with lineage-specific transcription factors, but little is known of how these cytokines might regulate the expression/activity of these different transcription factors. Here we identify the critical signal transduction pathways that mediate the IL-3 induced enhancement of retinoic acid (RA) receptor transcriptional activity that accompanies the IL-3 mediated commitment of the multipotent, stem cell factor (SCF)-dependent EML cell line to granulocyte/monocyte progenitors. We observe that the addition of IL-3 to EML cells induces activation of the PI3 kinase, MAP Kinase and Jak/Stat pathways and that Jak2 activation is the critical "proximal" mediator of the IL-3 induced enhancement of RA receptor activity. Constitutively active Stat5 constructs enhance both the transcriptional activity of RA receptors in EML cells and the commitment of these cells to granulocyte/monocyte progenitors, while dominant negative Stat5 constructs inhibit this IL-3 induced enhancement of RA receptor transcriptional activity. We observe that the retinoic acid response element (RARE) utilized in our RA responsive reporter harbors overlapping Stat/RA receptor binding sites. Moreover co-immunoprecipitation studies indicate an interaction between Stat5 and RA receptors that is IL-3 dependent. Thus Stat5 is an important mediator of the IL-3 induced enhancement of RA receptor transcriptional activity that accompanies the commitment of immature EML cells to the granulocyte/monocyte lineage. Cytokine-mediated physical and functional interactions between Stat5 and RA receptors may play critical roles in regulating different stages of hematopoiesis.
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