The PI3K regulatory subunits p55α and p50α regulate cell death in vivo
Cell Death and Differentiation
Nature Publishing Group
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Pensa, S., Neoh, K., Resemann, H., Kreuzaler, P., Abell, K., Clarke, N., Reinheckel, T., et al. (2014). The PI3K regulatory subunits p55α and p50α regulate cell death in vivo. Cell Death and Differentiation https://doi.org/10.1038/cdd.2014.59
The phosphatidylinositol 3-kinase (PI3K) regulatory subunits p55α and p50α are coordinately transcriptionally upregulated by signal transducer and activator of transcription 3 (Stat3) at the onset of mammary gland involution, a process that requires Stat3. Deletion of both p55α and p50α subunits in vivo abrogated mammary epithelial cell death during involution. This was associated also with reduced cytosolic levels and activity of the cysteine protease cathepsin L, which is implicated in lysosomal-mediated programmed cell death (LM-PCD) and is upregulated in involution. Furthermore, involution is delayed in cathepsin L-deficient mice suggesting that the p55α/p50α subunits mediate cell death in part by elevating the level of cathepsin L resulting in increased cytosolic activity. Surprisingly, we found that p55α/p50α localize to the nucleus where they bind to chromatin and regulate transcription of a subset of inflammatory/acute phase genes that are also Stat3 targets. Our findings reveal a novel role for these PI3K regulatory subunits as regulators of LM-PCD in vivo.
We thank Maximilian Blanck and Ivan Ferrer-Vicens for immunofluorescence studies, Helen Skelton for tissue histology and the Watson lab members for helpful discussions. This work was funded by BBSRC and MRC grants (BB/D012937/1 and MR/J001023/1) awarded to CJW, SP is the recipient of a Marie Curie IEF fellowship (EU Marie Curie grant no. 273365), KN was supported by a BBSRC CASE PhD studentship, HR is funded by a Cambridge Cancer Center PhD studentship and PAK is the recipient of a Trinity College fellowship. TR was supported by the Excellence Initiative of the German Federal and State Governments (EXC 294), and the Deutche Forschungsgemeinschaft SFB 850 project B7.
European Commission (273365)
External DOI: https://doi.org/10.1038/cdd.2014.59
This record's URL: https://www.repository.cam.ac.uk/handle/1810/245339