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Prepublished online as a Blood First Edition Paper on June 28, 2002; DOI 10.1182/blood-2001-12-0374.
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Blood, 15 December 2002, Vol. 100, No. 13, pp. 4401-4409
HEMATOPOIESIS
IL-3-induced enhancement of retinoic acid 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
From the Human Biology Division, Fred Hutchinson Cancer
Research Center, Seattle, WA.
The regulation of hematopoiesis involves the interaction of
specific hematopoietic cytokines with lineage-specific transcription factors, but little is known about how these cytokines might regulate the expression/activity of these different transcription factors. Here
we identify the critical signal transduction pathways that mediate the
interleukin 3 (IL-3)-induced enhancement of retinoic acid receptor
(RAR) 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
phosphatidylinositol-3 kinase, mitogen-activated protein kinase, and
Jak/Stat pathways and that Jak2 activation is the critical
"proximal" mediator of the IL-3-induced enhancement of RAR
activity. Constitutively active Stat5 constructs enhance both the
transcriptional activity of RARs in EML cells and the commitment of
these cells to granulocyte/monocyte progenitors, whereas
dominant-negative Stat5 constructs inhibit this IL-3-induced
enhancement of RAR transcriptional activity. We observe that the
retinoic acid response element (RARE) used in our RA responsive
reporter harbors overlapping Stat/RAR-binding sites. Moreover,
coimmunoprecipitation studies indicate an interaction between Stat5 and
RARs that is IL-3 dependent. Thus, Stat5 is an important mediator of
the IL-3-induced enhancement of RAR transcriptional activity that
accompanies the commitment of immature EML cells to the
granulocyte/monocyte lineage. Cytokine-mediated physical and functional
interactions between Stat5 and RARs may play critical roles in
regulating different stages of hematopoiesis.
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