title: The PI3K regulatory subunits p55α and p50α regulate cell death in vivo.
abstract: 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.
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: S
authors.initials: S
authors.lastname: Pensa
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: K
authors.initials: K
authors.lastname: Neoh
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: H K
authors.initials: HK
authors.lastname: Resemann
authors.affiliation: 1] Department of Pathology, University of Cambridge, Cambridge, UK [2] Department of Biochemistry, University of Cambridge, Cambridge, UK.
authors.forename: P A
authors.initials: PA
authors.lastname: Kreuzaler
authors.affiliation: 1] Department of Pathology, University of Cambridge, Cambridge, UK [2] LEO Pharma A/S Industriparken 55, Ballerup, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Abell
authors.affiliation: GlaxoSmithKline, Stevenage, UK.
authors.forename: N J
authors.initials: NJ
authors.lastname: Clarke
authors.affiliation: Institute of Molecular Medicine and Cell Research and BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Reinheckel
authors.affiliation: Joslin Diabetes Center, Boston, MA, USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Kahn
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: C J
authors.identifier: 0000000285485902
authors.initials: CJ
authors.lastname: Watson
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D021122:Protein Subunits; D019869:Phosphatidylinositol 3-Kinases