Musashi1 modulates mammary progenitor cell expansion through proliferin-mediated activation of the wnt and notch pathways

Xiao Yang Wang, Yuzhi Yin, Hongyan Yuan, Toshiyuki Sakamaki, Hideyuki Okano, Robert I. Glazer

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

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 CD24hi Sca-1+, CD24hi 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 β-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 β-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.

Original languageEnglish
Pages (from-to)3589-3599
Number of pages11
JournalMolecular and cellular biology
Volume28
Issue number11
DOIs
Publication statusPublished - 2008 Jun

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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