Musashi1 modulates mammary progenitor cell expansion through proliferin-mediated activation of the Wnt and Notch pathways.
The RNA-binding protein Musashi1 (Msi1) is a positive regulator of Notch-mediated transcription in Drosophila melanogaster and neural progenitor cells and has been identified as a putative human breast stem cell marker. Here we describe a novel functional role for Msi1: its ability to drive progenitor cell expansion along the luminal and myoepithelial lineages. Expression of Msi1 in mammary epithelial cells increases the abundance of CD24(hi) Sca-1(+), CD24(hi) CD29(+), CK19, CK6, and double-positive CK14/CK18 progenitor cells. Proliferation is associated with increased proliferin-1 (PLF1) and reduced Dickkopf-3 (DKK3) secretion into the conditioned medium from Msi-expressing cells, which is associated with increased colony formation and extracellular signal-regulated kinase (ERK) phosphorylation. Treatment with the MEK inhibitor U0126 inhibits ERK activation and decreases Notch and beta-catenin/T-cell factor (TCF) reporter activity resulting from Msi1 expression. Reduction of DKK3 in control cells with a short hairpin RNA (shRNA) increases Notch and beta-catenin/TCF activation, whereas reduction of PLF1 with a shRNA in Msi1-expressing cells inhibits these pathways. These results identify Msi1 as a key determinant of the mammary lineage through its ability to coordinate cell cycle entry and activate the Notch and Wnt pathways by a novel autocrine process involving PLF1 and DKK3.
Wang
Xiao-Yang
XY
Department of Oncology, Georgetown University, and Lombardi Comprehensive Cancer Center, Washington, DC 20007, USA.
Yin
Yuzhi
Y
Yuan
Hongyan
H
Sakamaki
Toshiyuki
T
Okano
Hideyuki
H
Glazer
Robert I
RI
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019898:Autocrine Communication; D002070:Butadienes / Q000494:pharmacology; D002448:Cell Adhesion / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation; D018507:Gene Expression Regulation, Developmental; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D011388:Prolactin; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002070:Butadienes; C405061:Dkk3 protein, mouse; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C104786:Msi1h protein, mouse; D009419:Nerve Tissue Proteins; D009570:Nitriles; C000634106:Prl2c2 protein, mouse; D047428:Protein Kinase Inhibitors; D016601:RNA-Binding Proteins; D051880:Receptors, Notch; C113580:U 0126; D051153:Wnt Proteins; D011388:Prolactin