BAD regulates mammary gland morphogenesis by 4E-BP1-mediated control of localized translation in mouse and human models

Autor: Lin Fu Zhu, Vrajesh Pandya, Raven Kirschenman, Namita Tripathi, Namrata Patel, Nika N. Danial, John Maringa Githaka, David A. Kramer, Rachel Montpetit, Nahum Sonenberg, D. Alan Underhill, Ing Swie Goping, Richard P. Fahlman
Rok vydání: 2021
Předmět:
0301 basic medicine
Messenger
General Physics and Astronomy
Cell Cycle Proteins
Inbred C57BL
environment and public health
Mice
0302 clinical medicine
Models
Cell Movement
Serine
Morphogenesis
Gene Knock-In Techniques
Phosphorylation
Tissue homeostasis
Cancer
Mice
Knockout
Pediatric
Multidisciplinary
Adaptor Proteins
Cell migration
Translation (biology)
Mammary Glands
Cell biology
Organoids
030220 oncology & carcinogenesis
Models
Animal
Female
bcl-Associated Death Protein
Human
Science
Knockout
1.1 Normal biological development and functioning
Repressor
Motility
Biology
General Biochemistry
Genetics and Molecular Biology
Article
Cell Line
Focal adhesion
03 medical and health sciences
Mammary Glands
Animal
Underpinning research
Breast Cancer
Animals
Humans
RNA
Messenger
Mammary Glands
Human
Adaptor Proteins
Signal Transducing
Animal
Signal Transducing
General Chemistry
Mice
Inbred C57BL
enzymes and coenzymes (carbohydrates)
030104 developmental biology
Amino Acid Substitution
Protein Biosynthesis
RNA
Mutant Proteins
Generic health relevance
Digestive Diseases
Mammary gland morphogenesis
Zdroj: Nature communications, vol 12, iss 1
Nature Communications
Nature Communications, Vol 12, Iss 1, Pp 1-18 (2021)
Popis: Elucidation of non-canonical protein functions can identify novel tissue homeostasis pathways. Herein, we describe a role for the Bcl-2 family member BAD in postnatal mammary gland morphogenesis. In Bad3SA knock-in mice, where BAD cannot undergo phosphorylation at 3 key serine residues, pubertal gland development is delayed due to aberrant tubulogenesis of the ductal epithelium. Proteomic and RPPA analyses identify that BAD regulates focal adhesions and the mRNA translation repressor, 4E-BP1. These results suggest that BAD modulates localized translation that drives focal adhesion maturation and cell motility. Consistent with this, cells within Bad3SA organoids contain unstable protrusions with decreased compartmentalized mRNA translation and focal adhesions, and exhibit reduced cell migration and tubulogenesis. Critically, protrusion stability is rescued by 4E-BP1 depletion. Together our results confirm an unexpected role of BAD in controlling localized translation and cell migration during mammary gland development.
Preventing phosphorylation of BAD (3SA) in mouse models and human cells inhibits mammary gland development, acting by disrupting 4E-BP1- mediated translation and affecting focal adhesion/protrusion stability, cell migration and ductal tubulogenesis.
Databáze: OpenAIRE
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