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Loss of SOCS3 gene expression converts STAT3 function from anti-apoptotic to pro-apoptotic.

Authors
  • Lu, Yang
  • Fukuyama, Satoru
  • Yoshida, Ryoko
  • Kobayashi, Takashi
  • Saeki, Kazuko
  • Shiraishi, Hiroshi
  • Yoshimura, Akihiko
  • Takaesu, Giichi
Type
Published Article
Journal
Journal of Biological Chemistry
Publisher
American Society for Biochemistry & Molecular Biology (ASBMB)
Publication Date
Dec 01, 2006
Volume
281
Issue
48
Pages
36683–36690
Identifiers
PMID: 17028185
Source
Medline
License
Unknown

Abstract

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 p50alpha and p55alpha 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 p50alpha and p55alpha 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.

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