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Blood, 1 March 2002, Vol. 99, No. 5, pp. 1627-1637
HEMATOPOIESIS
Differential expression and phosphorylation of distinct STAT3
proteins during granulocytic differentiation
Diane L. Hevehan,
William
M. Miller, and
Eleftherios T. Papoutsakis
From the Department of Chemical Engineering,
Northwestern University, Evanston, IL.
External stimuli act in concert with intracellular signals to
regulate a cell's genetic program, activating genes important in
granulocytic lineage commitment, proliferation, and maturation. Signal
transducer and activator of transcription 3 (STAT3), a transcription
factor, has been implicated in mediating granulocytic differentiation.
We have examined the role of STAT3 as a physiologic mediator of
granulocytic kinetics. Distinct isoforms the long form STAT3 , the
truncated forms STAT3 and STAT3 , and a putative novel form
STAT3 were expressed and activated in a maturation stage-specific
manner. With the progression of differentiation, the ratio of isoforms
shifted from predominantly STAT3 to STAT3. The kinetics of
STAT3, generated through proteolytic cleavage of STAT3, coincided
with but were inverse to those of STAT3. STAT3 was expressed at
low levels and decreased with differentiation but was preferentially
phosphorylated during an intermediate stage of maturation. Under
different culture conditions (pH, O2 tension [pO2], IL-3), we found that the expression and
phosphorylation status of the different STAT3 isoforms displayed unique
kinetic patterns that correlated with the effects on granulocyte
differentiation. The evidence suggests that signals triggered by pH,
pO2, and IL-3 each converge on STAT3 through independent
mechanisms, exploiting the flexibility granted by the diversity in
expression and phosphorylation of the different STAT3 isoforms, to
regulate distinct granulocytic cell responses. The selective expression
of STAT3 isoforms and their activation is a major determinant of
granulocytic cell development and provides a molecular basis for
evaluating the effects of various environmental factors on the
STAT3-mediated signaling pathway.
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