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Blood, Vol. 93 No. 12 (June 15), 1999:
pp. 4154-4166
Dominant Negative Mutants Implicate STAT5 in Myeloid Cell
Proliferation and Neutrophil Differentiation
Robert L. Ilaria Jr,
Robert G. Hawley, and
Richard A. Van Etten
From The Simmons Cancer Center, University of Texas Southwestern
Medical School, Dallas, TX; the Hematopoiesis Department, Holland
Laboratory, American Red Cross, Rockville, MD; and The Center for Blood
Research, Department of Genetics, Harvard Medical School, Boston, MA.
STAT5 is a member of the signal transducers and activation of
transcription (STAT) family of latent transcription factors activated
in a variety of cytokine signaling pathways. We introduced alanine
substitution mutations in highly conserved regions of murine STAT5A and
studied the mutants for dimerization, DNA binding, transactivation, and
dominant negative effects on erythropoietin-induced STAT5-dependent
transcriptional activation. The mutations included two near the
amino-terminus (W255KR AAA and
R290QQAAA), two in the DNA-binding domain
(E437EAA and V466VVAAA),
and a carboxy-terminal truncation of STAT5A (STAT5A/ 53C) analogous
to a naturally occurring isoform of rat STAT5B. All of the STAT mutant
proteins were tyrosine phosphorylated by JAK2 and heterodimerized with
STAT5B except for the WKR mutant, suggesting an important role for this
region in STAT5 for stabilizing dimerization. The WKR, EE, and VVV
mutants had no detectable DNA-binding activity, and the WKR and VVV
mutants, but not EE, were defective in transcriptional induction. The
VVV mutant had a moderate dominant negative effect on
erythropoietin-induced STAT5 transcriptional activation, which was
likely due to the formation of heterodimers that are defective in DNA
binding. Interestingly, the WKR mutant had a potent dominant negative
effect, comparable to the transactivation domain deletion mutant,
53C. Stable expression of either the WKR or 53C STAT5 mutants in
the murine myeloid cytokine-dependent cell line 32D inhibited both
interleukin-3-dependent proliferation and granulocyte
colony-stimulating factor (G-CSF)-dependent differentiation, without
induction of apoptosis. Expression of these mutants in primary murine
bone marrow inhibited G-CSF-dependent granulocyte colony formation in
vitro. These results demonstrate that mutations in distinct regions of
STAT5 exert dominant negative effects on cytokine signaling, likely
through different mechanisms, and suggest a role for STAT5 in
proliferation and differentiation of myeloid cells.
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