BIM Regulates Apoptosis during Mammary Ductal Morphogenesis, and Its Absence Reveals Alternative Cell Death Mechanisms
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The adult, virgin mammary gland is a highly organized tree-like structure formed by ducts with hollowed lumen. Although lumen formation during pubertal development appears to involve apoptosis, the molecular mechanisms that regulate this process are not known. Here, we demonstrate that disruption of the BH3-only proapoptotic factor Bim in mice prevents induction of apoptosis in and clearing of the lumen in terminal end buds during puberty. However, cells that fill the presumptive luminal space are eventually cleared from the adjacent ducts by a caspase-independent death process. Within the filled Bim(-/-) ducts, epithelial cells are deprived of matrix attachment and undergo squamous differentiation prior to clearing. Similarly, we also detect squamous differentiation in vitro when immortalized mammary epithelial cells are detached from the matrix. These data provide important mechanistic information on the processes involved in sculpting the mammary gland and demonstrate that BIM is a critical regulator of apoptosis in vivo.
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At least in some settings, detachment from the extracellular matrix triggers MOMP upon activation of the BH3-only proteins BIM and BMF.
“At least in some settings, detachment from the extracellular matrix triggers MOMP upon activation of the BH3-only proteins BIM and BMF [137, 235].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [235]
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- Authors
- Mailleux, A. A., Overholtzer, M., Schmelzle, T., Bouillet, P., Strasser, A., & Brugge, J. S.
- Affiliations
- Harvard University (US)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Corresponding author
- Brugge, Joan S.
- ORCID
- Venue
- Developmental Cell
- Publisher
- Elsevier BV
- Published
- 2007-02
- Volume
- 12
- Issue
- 2
- Pages
- 221-234
- ISSN
- 1534-5807 (ISSN-L)
- PMC
- PMC2698712
- OpenAlex
- W2085836692
- Cited by
- 255
- References
- 24
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 7 · 2023: 19 · 2022: 11 · 2021: 9 · 2020: 13 · 2019: 5 · 2018: 8 · 2017: 13 · 2016: 17 · 2015: 19 · 2014: 14 · 2013: 14 · 2012: 14
- FWCI
- 7.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2358 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Developmental Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (PA00A-105094)
- National Cancer Institute (CA080111, CA105134)
- Fondation pour la Recherche Médicale
- Leukemia and Lymphoma Society
- Sylvia and Charles Viertel Charitable Foundation (T32CA09361)
- Susan G. Komen (PDF29406)
- National Health and Medical Research Council (257502)
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- building information modeling, apoptosis, mammary gland development, terminal end buds, lumen formation, caspase-independent cell death, squamous differentiation, mammary epithelial cells, pubertal development, BH3-only proteins
- MeSH terms
- Bcl-2-Like Protein 11, Animals, Cell Differentiation, Embryo, Mammalian, Epithelial Cells, Female, Humans, Mammary Glands, Animal, Membrane Proteins, Mice, Inbred C57BL, Morphogenesis, Proto-Oncogene Proteins, Puberty, Time Factors, Apoptosis, Caspases, Anoikis, Cell Proliferation, Apoptosis Regulatory Proteins, Mice
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