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

Abstract

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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Acknowledgements

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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The authors declare no competing financial interests.

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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). https://doi.org/10.1038/ncb1242

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