CIS, a cytokine inducible SH2 protein, is a target of the JAK-STAT5 pathway and modulates STAT5 activation

Akira Matsumoto, Masaaki Masuhara, Kaoru Mitsui, Masahiro Yokouchi, Motoaki Ohtsubo, Hiroyuki Misawa, Atsushi Miyajima, Akihiko Yoshimura

Research output: Contribution to journalArticle

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Abstract

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 STATS 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 STATS 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.

Original languageEnglish
Pages (from-to)3148-3154
Number of pages7
JournalBlood
Volume89
Issue number9
Publication statusPublished - 1997 May 1
Externally publishedYes

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Erythropoietin
Chemical activation
Cytokines
Erythropoietin Receptors
Tyrosine
Phosphorylation
Proteins
Genes
HEK293 Cells
Interleukin-3 Receptors
Oncostatin M
Cytokine Receptors
src Homology Domains
Interleukin-2 Receptors
Interleukin-3
5' Flanking Region
Transcription Initiation Site
Luciferases
Modulators
Interleukin-2

ASJC Scopus subject areas

  • Hematology

Cite this

Matsumoto, A., Masuhara, M., Mitsui, K., Yokouchi, M., Ohtsubo, M., Misawa, H., ... Yoshimura, A. (1997). CIS, a cytokine inducible SH2 protein, is a target of the JAK-STAT5 pathway and modulates STAT5 activation. Blood, 89(9), 3148-3154.

CIS, a cytokine inducible SH2 protein, is a target of the JAK-STAT5 pathway and modulates STAT5 activation. / Matsumoto, Akira; Masuhara, Masaaki; Mitsui, Kaoru; Yokouchi, Masahiro; Ohtsubo, Motoaki; Misawa, Hiroyuki; Miyajima, Atsushi; Yoshimura, Akihiko.

In: Blood, Vol. 89, No. 9, 01.05.1997, p. 3148-3154.

Research output: Contribution to journalArticle

Matsumoto, A, Masuhara, M, Mitsui, K, Yokouchi, M, Ohtsubo, M, Misawa, H, Miyajima, A & Yoshimura, A 1997, 'CIS, a cytokine inducible SH2 protein, is a target of the JAK-STAT5 pathway and modulates STAT5 activation', Blood, vol. 89, no. 9, pp. 3148-3154.
Matsumoto A, Masuhara M, Mitsui K, Yokouchi M, Ohtsubo M, Misawa H et al. CIS, a cytokine inducible SH2 protein, is a target of the JAK-STAT5 pathway and modulates STAT5 activation. Blood. 1997 May 1;89(9):3148-3154.
Matsumoto, Akira ; Masuhara, Masaaki ; Mitsui, Kaoru ; Yokouchi, Masahiro ; Ohtsubo, Motoaki ; Misawa, Hiroyuki ; Miyajima, Atsushi ; Yoshimura, Akihiko. / CIS, a cytokine inducible SH2 protein, is a target of the JAK-STAT5 pathway and modulates STAT5 activation. In: Blood. 1997 ; Vol. 89, No. 9. pp. 3148-3154.
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AU - Yokouchi, Masahiro

AU - Ohtsubo, Motoaki

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AU - Yoshimura, Akihiko

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