The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/1/63/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 1, January 4, 1999 63-73

Articles

STAT3 Is Required for the gp130-mediated Full Activation of the c-myc Gene

Nobuo Kiuchi, Koichi Nakajima, Makoto Ichiba, Toshiyuki Fukada, Masahiro Narimatsu, Katsunori Mizuno, Masahiko Hibi, and Toshio Hirano

From the Division of Molecular Oncology, Biomedical Research Center, Osaka University Medical School, Suita, Osaka 565-0871, Japan

The signal transducers and activators of transcription (STAT) family members have been implicated in regulating the growth, differentiation, and death of normal and transformed cells in response to either extracellular stimuli, including cytokines and growth factors, or intracellular tyrosine kinases. c-myc expression is coordinately regulated by multiple signals in these diverse cellular responses. We show that STAT3 mostly mediates the rapid activation of the c-myc gene upon stimulation of the interleukin (IL)-6 receptor or gp130, a signal transducing subunit of the receptor complexes for the IL-6 cytokine family. STAT3 does so most likely by binding to cis-regulatory region(s) of the c-myc gene. We show that STAT3 binds to a region overlapping with the E2F site in the c-myc promoter and this site is critical for the c-myc gene promoter– driven transcriptional activation by IL-6 or gp130 signals. This is the first identification of the linkage between a member of the STAT family and the c-myc gene activation, and also explains how the IL-6 family of cytokines is capable of inducing the expression of the c-myc gene.

Key Words: signal transducer and activator of transcription 3 • c-myc • promoter • interleukin 6 • gp130

Address correspondence to Toshio Hirano, Division of Molecular Oncology, Biomedical Research Center, Osaka University Medical School, 2-2, Yamada-oka, Suita, Osaka 565-0871, Japan. Phone: 81-6-879-3880; Fax: 81-6-879-3889; E-mail: hirano{at}molonc.med.osaka-u.ac.jp

K. Nakajima's present address is the Department of Immunology, Osaka City University Medical School, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.

1 Abbreviations used in this paper: Ad, adenovirus; APRE, acute phase response element; EMSA, electromobility shift assay; G-CSF, granulocyte colony-stimulating factor; G-CSFR, G-CSF receptor; HA, hemagglutinin; JAK, Janus tyrosine kinases; PDGF, platelet-derived growth factor; pRb, products of the retinoblastoma gene; SHP-2, SH2 domain containing phosphatase; STAT, signal transducers and activators of transcription.


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