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J. Biol. Chem., Vol. 280, Issue 13, 12621-12629, April 1, 2005

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Signal Transducers and Activators of Transcription 3 Augments the Transcriptional Activity of CCAAT/Enhancer-binding Protein in Granulocyte Colony-stimulating Factor Signaling Pathway^*

Akihiko Numata, Kazuya Shimoda, Kenjiro Kamezaki, Takashi Haro, Haruko Kakumitsu, Koutarou Shide, Kouji Kato, Toshihiro Miyamoto, Yoshihiro Yamashita¶, Yasuo Oshima||, Hideaki Nakajima**, Atsushi Iwama, Kenichi Aoki, Ken Takase, Hisashi Gondo, Hiroyuki Mano¶, and Mine Harada

From the Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka, 812-8582, the ^¶Division of Functional Genomics, Jichi Medical School, 3311-1 Yakushiji, Kawaguchi-gun, Tochigi, 329-0498, the ^||Department of Clinical Pharmacology, Jichi Medical School, 3311-1 Yakushiji, Kawaguchi-gun, Tochigi, 329-0498, the ^**Department of Hematopoietic Factors, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, and the Laboratory of Stem Cell Therapy, Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan

The Janus kinase (Jak)-Stat pathway plays an essential role in cytokine signaling. Granulocyte colony-stimulating factor (G-CSF) promotes granulopoiesis and granulocytic differentiation, and Stat3 is the principle Stat protein activated by G-CSF. Upon treatment with G-CSF, the interleukin-3-dependent cell line 32D clone 3(32Dcl3) differentiates into neutrophils, and 32Dcl3 cells expressing dominant-negative Stat3 (32Dcl3/DNStat3) proliferate in G-CSF without differentiation. Gene expression profile and quantitative PCR analysis of G-CSF-stimulated cell lines revealed that the expression of C/EBP was up-regulated by the activation of Stat3. In addition, activated Stat3 bound to CCAAT/enhancer-binding protein (C/EBP), leading to the enhancement of the transcription activity of C/EBP. Conditional expression of C/EBP in 32Dcl3/DNStat3 cells after G-CSF stimulation abolishes the G-CSF-dependent cell proliferation and induces granulocytic differentiation. Although granulocyte-specific genes, such as the G-CSF receptor, lysozyme M, and neutrophil gelatinase-associated lipocalin precursor (NGAL) are regulated by Stat3, only NGAL was induced by the restoration of C/EBP after stimulation with G-CSF in 32Dcl3/DNStat3 cells. These results show that one of the major roles of Stat3 in the G-CSF signaling pathway is to augment the function of C/EBP, which is essential for myeloid differentiation. Additionally, cooperation of C/EBP with other Stat3-activated proteins are required for the induction of some G-CSF responsive genes including lysozyme M and the G-CSF receptor.

Received for publication, July 26, 2004 , and in revised form, January 3, 2005.

^* This work was supported by a grant of the Japan Leukemia Research Foundation (2002) and Grants-in-aid for Scientific Research 11307015 and 15390302 from the Ministry of Education, Science, Sports, and Culture in Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 81-92-642-5230; Fax: 81-92-642-5247; E-mail: kshimoda{at}intmed1.med.kyushu-u.ac.jp.

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