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J. Biol. Chem., Vol. 281, Issue 48, 36683-36690, December 1, 2006

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Loss of SOCS3 Gene Expression Converts STAT3 Function from Anti-apoptotic to Pro-apoptotic^*

From the Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

The transcription factor STAT3 is activated by interleukin-6-related cytokines and has been implicated as an oncogene; it promotes cell proliferation and is anti-apoptotic. However, in some cases, STAT3 has been shown to be pro-apoptotic, especially in mammary epithelial cells. In this report, we generated SOCS3-deficient murine embryonic fibroblasts (MEFs), in which STAT3 activation is extremely enhanced and prolonged. We found that LIF induces caspase-3 activation and apoptosis of SOCS3^–/– MEFs. Exogenous expression of the dominant negative form of STAT3 but not STAT1 suppressed LIF-induced apoptosis of SOCS3^–/– MEFs, indicating that STAT3 plays a critical role in apoptosis induction. As shown in mammary gland epithelial cells, expression of the phosphatidylinositol 3-kinase regulatory subunits p50 and p55 was induced in response to LIF in SOCS3^–/– MEFs but not in wild-type MEFs, and Akt/protein kinase B activity was substantially reduced in SOCS3^–/– MEFs. Furthermore, we found that some of the STAT3 target genes related to apoptosis and proliferation, such as Bcl-2 and cyclin D1, were repressed upon LIF treatment in SOCS3^–/– cells. Not only the up-regulation of p50 and p55 but also the repression of cyclin D1 and Bcl-2 in SOCS3^–/– MEFs was inhibited by dominant negative STAT3. These data suggest that prolonged activation of STAT3 could induce apoptosis/growth arrest rather than anti-apoptosis and proliferation in certain cases, and SOCS3 is a critical regulator of this balance.

Received for publication, August 3, 2006 , and in revised form, October 6, 2006.

^* This work was supported by special grants-in-aid from the Ministry of Education, Science Technology, Sports, and Culture of Japan; the Haraguchi Memorial Foundation; the Yamanouchi Foundation for Research on Metabolic Disorders; the Takeda Science Foundation; the Mochida Memorial Foundation; the Kato Memorial Foundation; and the Uehara Memorial Foundation. 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.

¹ To whom correspondence should be addressed. Tel.: 81-92-642-6822; Fax: 81-92-642-6825; E-mail: takaesug{at}bioreg.kyushu-u.ac.jp.

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