Beta1 integrins regulate mammary gland proliferation and maintain the integrity of mammary alveoli.
Integrin-extracellular matrix interactions play important roles in the coordinated integration of external and internal cues that are essential for proper development. To study the role of beta1 integrin in the mammary gland, Itgbeta1(flox/flox) mice were crossed with WAPiCre transgenic mice, which led to specific ablation of beta1 integrin in luminal alveolar epithelial cells. In the beta1 integrin mutant mammary gland, individual alveoli were disorganized resulting from alterations in cell-basement membrane associations. Activity of focal adhesion kinase (FAK) was also decreased in mutant mammary glands. Luminal cell proliferation was strongly inhibited in beta1 integrin mutant glands, which correlated with a specific increase of p21 Cip1 expression. In a p21 Cip1 null background, there was a partial rescue of BrdU incorporation, providing in vivo evidence linking p21 Cip1 to the proliferative defect observed in beta1 integrin mutant glands. A connection between p21 Cip1 and beta1 integrin as well as FAK was also established in primary mammary cells. These results point to the essential role of beta1 integrin signaling in mammary epithelial cell proliferation.
Li
Na
N
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Zhang
Yu
Y
Naylor
Matthew J
MJ
Schatzmann
Franziska
F
Maurer
Francisca
F
Wintermantel
Tim
T
Schuetz
Gunther
G
Mueller
Ulrich
U
Streuli
Charles H
CH
Hynes
Nancy E
NE
D000818:Animals; D017209:Apoptosis; D001485:Basement Membrane / Q000648:ultrastructure; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D002999:Clone Cells / Q000166:cytology; D003433:Crosses, Genetic; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004261:DNA Replication; D004847:Epithelial Cells / Q000166:cytology; D005260:Female; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D018390:Gene Targeting; D019012:Integrin beta1 / Q000235:genetics / Q000502:physiology*; D007774:Lactation; D008321:Mammary Glands, Animal / Q000002:abnormalities / Q000166:cytology* / Q000637:transplantation; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009024:Morphogenesis; D011247:Pregnancy; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D013234:Stem Cells / Q000166:cytology
C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019012:Integrin beta1; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse