title: The BH3-only protein BIM contributes to late-stage involution in the mouse mammary gland.
abstract: After cessation of lactation, involution of the mouse mammary gland proceeds in two distinct phases, a reversible and an irreversible one, which leads to the death and removal of alveolar cells. Cell death is preceded by the loss of STAT5 activity, which abrogates cell differentiation and gain of STAT3 activity. Despite early observations implicating BCL2 (B cell lymphoma 2) family proteins in this process, recent evidence suggests that STAT3-controlled cathepsin activity is most critical for cell death at the early stage of involution. Somewhat surprisingly, this cell death associates with but does not depend on the activation of pro-apoptotic effector caspases. However, transgenic overexpression of BCL2, that blocks caspase activation, delays involution while conditional deletion of BclX accelerates this process, suggesting that BCL2 family proteins are needed for the effective execution of involution. Here, we report on the transcriptional induction of multiple pro-apoptotic BCL2 family proteins of the 'BH3-only' subgroup during involution and the rate-limiting role of BIM in this process. Loss of Bim delayed epithelial cell clearance during involution after forced weaning in mice, whereas the absence of related Bmf had minor and loss of Bad or Noxa no impact on this process. Consistent with a contribution of BCL2 family proteins to the second wave of cell death during involution, loss of Bim reduced the number of apoptotic cells in this irreversible phase. Notably, the expression changes observed within the BCL2 family did not depend on STAT3 signalling, in line with its initiating role early in the process, but rather appear to result from relief of repression by STAT5. Our findings support the existence of a signalling circuitry regulating the irreversible phase of involution in mice by engaging BH3-only protein-driven mitochondrial apoptosis.
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: F
authors.initials: F
authors.lastname: Schuler
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: F
authors.initials: F
authors.lastname: Baumgartner
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: V
authors.initials: V
authors.lastname: Klepsch
authors.affiliation: Department of Obstetrics & Gynecology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Chamson
authors.affiliation: Department of Obstetrics & Gynecology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: E
authors.initials: E
authors.lastname: Müller-Holzner
authors.affiliation: Department of Pathology, Tennis Court Road, University of Cambridge, Cambridge CB2 1QP, UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: Watson
authors.affiliation: Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: S
authors.initials: S
authors.lastname: Oh
authors.affiliation: Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: L
authors.initials: L
authors.lastname: Hennighausen
authors.affiliation: Division of Medical Biochemistry, Biocenter, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Tymoszuk
authors.affiliation: Division of Medical Biochemistry, Biocenter, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: W
authors.initials: W
authors.lastname: Doppler
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Villunger
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D020169:Caspases / Q000096:biosynthesis; D016923:Cell Death / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D007774:Lactation / Q000235:genetics / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000254:growth & development / Q000378:metabolism*; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050799:STAT5 Transcription Factor; D020169:Caspases