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CIS, a cytokine inducible SH2 protein, is a target of the JAK-STAT5 pathway
and modulates STAT5 activation
A Matsumoto, M Masuhara, K Mitsui, M Yokouchi, M Ohtsubo, H Misawa, A Miyajima and A Yoshimura
Insititute of Life Science, Kurume University, Japan.
We searched for immediate early cytokine responsive genes and isolated a
novel gene, CIS (Cytokine Inducible SH2 containing protein) that is induced
in hematopoietic cells by a subset of cytokines including interleukin-2
(IL-2), IL-3, and erythropoietin (EPO). The mutant IL-2 receptor that fails
to activate STAT5 could not induce CIS, suggesting that STAT5 is involved
in the cytokine-inducible expression of CIS. We cloned the 5'-flanking
region of the CIS gene and found that about 200 bases upstream of the
transcription-initiation site contain four potential STAT5 binding sites
(MGF boxes). Luciferase reporter assays showed that these MGF boxes were
essential for EPO-dependent promoter activity. Expression of STAT5 and the
EPO receptor in HEK293 cells conferred EPO-dependent activation of the CIS
promoter. These data indicate that CIS is a target of the JAK-STAT5 pathway
of cytokine receptors. CIS contains an SH2 domain and binds to tyrosine-
phosphorylated EPO and IL-3 receptors. In HEK293 cells expressing STAT5 and
the EPO receptor, EPO-dependent tyrosine phosphorylation of STAT5, as well
as EPO-dependent CIS-promoter activation, was suppressed when CIS was
coexpressed. Moreover, the induction of oncostatin M, another STAT5 target,
as well as the tyrosine-phosphorylation of STAT5, were partially suppressed
by CIS expression in Ba/F3 cells. Thus, CIS is a feedback modulator of
STAT5; its expression is induced by STAT5 and it negatively modulates STAT5
activation.
Volume 89,
Issue 9,
pp. 3148-3154,
05/01/1997
Copyright © 1997 by The American Society of Hematology
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