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

Yang Lu, Satoru Fukuyama, Ryoko Yoshida, Takashi Kobayashi, Kazuko Saeki, Hiroshi Shiraishi, Akihiko Yoshimura, Giichi Takaesu

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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 p50α and p55α 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 p50α and p55α 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.

Original languageEnglish
Pages (from-to)36683-36690
Number of pages8
JournalJournal of Biological Chemistry
Volume281
Issue number48
DOIs
Publication statusPublished - 2006 Dec 1
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Lu, Y., Fukuyama, S., Yoshida, R., Kobayashi, T., Saeki, K., Shiraishi, H., Yoshimura, A., & Takaesu, G. (2006). Loss of SOCS3 gene expression converts STAT3 function from anti-apoptotic to pro-apoptotic. Journal of Biological Chemistry, 281(48), 36683-36690. https://doi.org/10.1074/jbc.M607374200