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Stat3-induced apoptosis requires a molecular switch in PI(3)K subunit composition


Physiological apoptosis is induced by a switch from survival to death signalling. Dysregulation of this process is frequently associated with cancer1. A powerful model for this apoptotic switch is mammary gland involution, during which redundant milk-producing epithelial cells undergo apoptosis2. Signal transducer and activator of transcription 3 (Stat3) is an essential mediator of this switch but the mechanism has not yet been defined3. Stat3-dependent cell death during involution can be blocked by activation of Akt/protein kinase B (PKB)4, a downstream effector of the phosphoinositide-3-OH kinase (PI(3)K) pathway5. Here we show that expression of the PI(3)K regulatory subunits p55α and p50α is induced by Stat3 during involution. In the absence of Stat3 in vivo, upregulation of p55α and p50α is abrogated, levels of activated Akt are sustained and apoptosis is prevented. Chromatin immunoprecipitation assays show that Stat3 binds directly to the p55α and p50α promoters in vivo. Overexpression of either p55α or p50α reduces levels of activated Akt. We propose a novel mechanism in which Stat3 regulates apoptosis by inducing expression of distinct PI(3)K regulatory subunits to downregulate PI(3)K-Akt-mediated survival signalling.

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Figure 1: Activity of PI(3)K-Akt and Stat3 pathways during the apoptotic switch in mammary glands.
Figure 2: Differential expression of PI(3)K regulatory and catalytic subunits across the apoptotic switch.
Figure 3: p55α and p50α are transcriptional targets of Stat3 in vivo.
Figure 4: Stat3 regulates transcription of p55α and p50α in mammary, but not ES cells.
Figure 5: Expression of p55α and p50α is directly regulated by Stat3 in vivo and reduces levels of pAkt in vitro.

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  1. Schulze-Bergkamen, H. & Krammer, P. H. Apoptosis in cancer-implications for therapy. Semin. Oncol. 31, 90–119 (2004).

    Article  CAS  Google Scholar 

  2. Kumar, R., Vadlamudi, R. K. & Adam, L. Apoptosis in mammary gland and cancer. Endocr. Relat. Cancer 7, 257–269 (2000).

    Article  CAS  Google Scholar 

  3. Chapman, R. S. et al. Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3. Genes Dev. 13, 2604–2616 (1999).

    Article  CAS  Google Scholar 

  4. Schwertfeger, K. L., Richert, M. M. & Anderson, S. M. Mammary gland involution is delayed by activated Akt in transgenic mice. Mol. Endocrinol. 15, 867–881 (2001).

    Article  CAS  Google Scholar 

  5. Franke, T. F. et al. The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 2, 727–736 (1995).

    Article  Google Scholar 

  6. Levy, D. E. & Darnell, J. E. Jr. Stats: transcriptional control and biological impact. Nature Rev. Mol. Cell Biol. 3, 651–662 (2002).

    Article  CAS  Google Scholar 

  7. Kritikou, E. A. et al. A dual, non-redundant, role for LIF as a regulator of development and STAT3-mediated cell death in mammary gland. Development 130, 3459–3468 (2003).

    Article  CAS  Google Scholar 

  8. Yu, H. & Jove, R. The STATs of cancer - new molecular targets come of age. Nature Rev. Cancer 4, 97–105 (2004).

    Article  CAS  Google Scholar 

  9. Stambolic, V. et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95, 29–39 (1998).

    Article  CAS  Google Scholar 

  10. Otsu, M. et al. Characterization of two 85 kd proteins that associate with receptor tyrosine kinases, middle-T/pp60c-src complexes, and PI3-kinase. Cell 65, 91–104 (1991).

    Article  CAS  Google Scholar 

  11. Pons, S. et al. The structure and function of p55PIK reveal a new regulatory subunit for phosphatidylinositol 3-kinase. Mol. Cell Biol. 15, 4453–4465 (1995).

    Article  CAS  Google Scholar 

  12. Antonetti, D. A., Algenstaedt, P. & Kahn, C. R. Insulin receptor substrate 1 binds two novel splice variants of the regulatory subunit of phosphatidylinositol 3-kinase in muscle and brain. Mol. Cell Biol. 16, 2195–2203 (1996).

    Article  CAS  Google Scholar 

  13. Inukai, K. et al. A novel 55-kDa regulatory subunit for phosphatidylinositol 3-kinase structurally similar to p55PIK is generated by alternative splicing of the p85 gene. J. Biol. Chem. 271, 5317–5320 (1996).

    Article  CAS  Google Scholar 

  14. Fruman, D. A., Cantley, L. C. & Carpenter, C. L. Structural organization and alternative splicing of the murine phosphoinositide 3-kinase p85 alpha gene. Genomics 37, 113–121 (1996).

    Article  CAS  Google Scholar 

  15. Inukai, K. et al. p85 gene generates three isoforms of regulatory subunit for phosphatidylinositol 3-kinase (PI 3-Kinase), p50, p55, and p85, with different PI 3-kinase activity elevating responses to insulin. J. Biol. Chem. 272, 7873–7882 (1997).

    Article  CAS  Google Scholar 

  16. Vanhaesebroeck, B., Leevers, S. J., Panayotou, G. & Waterfield, M. D. Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends Biochem. Sci. 22, 267–272 (1997).

    Article  CAS  Google Scholar 

  17. Cantley, L. C. The phosphoinositide 3-kinase pathway. Science 296, 1655–1657 (2002).

    Article  CAS  Google Scholar 

  18. Ueki, K., Algenstaedt, P., Mauvais-Jarvis, F. & Kahn, C. R. Positive and negative regulation of phosphoinositide 3-kinase-dependent signaling pathways by three different gene products of the p85 regulatory subunit. Mol. Cell Biol. 20, 8035–8046 (2000).

    Article  CAS  Google Scholar 

  19. Ueki, K. et al. Molecular balance between the regulatory and catalytic subunits of phosphoinositide 3-kinase regulates cell signaling and survival. Mol. Cell Biol. 22, 965–977 (2002).

    Article  CAS  Google Scholar 

  20. Inukai, K. et al. Five isoforms of the phosphatidylinositol 3-kinase regulatory subunit exhibit different associations with receptor tyrosine kinases and their tyrosine phosphorylations. FEBS Lett. 490, 32–38 (2001).

    Article  CAS  Google Scholar 

  21. O'Farrell, A. M., Liu, Y., Moore, K. W. & Mui, A. L. IL-10 inhibits macrophage activation and proliferation by distinct signaling mechanisms: evidence for Stat3-dependent and -independent pathways. EMBO J. 16, 1006–1018 (1998).

    Article  Google Scholar 

  22. Leaman, D. W. et al. Roles of JAKs in activation of STATs and stimulation of c-fos gene expression by epidermal growth factor. Mol. Cell Biol. 16, 369–375 (1996).

    Article  CAS  Google Scholar 

  23. Niwa, H., Burdon, T., Chambers, I. & Smith, A. Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev. 12, 2048–2060 (1998).

    Article  CAS  Google Scholar 

  24. Burdon, T., Smith, A. & Savatier, P. Signalling, cell cycle and pluripotency in embryonic stem cells. Trends Cell Biol. 12, 432–438 (2002).

    Article  CAS  Google Scholar 

  25. Hallmann, D. et al. Altered signaling and cell cycle regulation in embryonal stem cells with a disruption of the gene for phosphoinositide 3-kinase regulatory subunit p85. J. Biol. Chem. 278, 5099–5108 (2003).

    Article  CAS  Google Scholar 

  26. Kerouz, N. J., Horsch, D., Pons, S. & Kahn, C. R. Differential regulation of insulin receptor substrates-1 and -2 (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase isoforms in liver and muscle of the obese diabetic (ob/ob) mouse. J. Clin. Invest. 100, 3164–3172 (1997).

    Article  CAS  Google Scholar 

  27. Torbenson, M. et al. STAT-3 overexpression and p21 up-regulation accompany impaired regeneration of fatty livers. Am. J. Pathol. 161, 155–161 (2002).

    Article  CAS  Google Scholar 

  28. Dani, C. et al. Paracrine induction of stem cell renewal by LIF-deficient cells: a new ES cell regulatory pathway. Dev. Biol. 203, 149–162 (1998).

    Article  CAS  Google Scholar 

  29. Vanhaesebroeck, B. et al. Distinct PI(3)Ks mediate mitogenic signalling and cell migration in macrophages. Nature Cell Biol. 1, 69–71 (1999).

    Article  CAS  Google Scholar 

  30. Davuluri, R. V., Grosse, I. & Zhang, M. Q. Computational identification of promoters and first exons in the human genome. Nature Genet. 4, 412–417 (2001). Erratum in Nature Genet. 3, 459 (2002).

    Article  Google Scholar 

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This work was supported by BBSRC grant number G18086. A.B. was supported by the Ludwig Institute for Cancer Research and by FIRB 2001 (Italy). We thank P. Came and F. Baxter for providing the TUNEL data, T. Rich and B. Kedjouar for critical reading of the manuscript, D. Vetrie for advice on ChIP assay, and A. Tolkovsky and C. Goemans for help with the adenovirus assays.

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Correspondence to Christine J. Watson.

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Abell, K., Bilancio, A., Clarkson, R. et al. Stat3-induced apoptosis requires a molecular switch in PI(3)K subunit composition. Nat Cell Biol 7, 392–398 (2005).

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