Metalloprotease-disintegrin ADAM12 expression is regulated by Notch signaling via microRNA-29

J Biol Chem. 2011 Jun 17;286(24):21500-10. doi: 10.1074/jbc.M110.207951. Epub 2011 Apr 25.


Metalloprotease-disintegrin ADAM12 is overexpressed and frequently mutated in breast cancer. We report here that ADAM12 expression in cultured mammalian cells is up-regulated by Notch signals. Expression of a constitutively active form of Notch1 in murine fibroblasts, myoblasts, or mammary epithelial cells or activation of the endogenous Notch signaling by co-culture with ligand-expressing cells increases ADAM12 protein and mRNA levels. Up-regulation of ADAM12 expression by Notch requires new transcription, is activated in a CSL-dependent manner, and is abolished upon inhibition of IκB kinase. Expression of a constitutively active Notch1 in NIH3T3 cells increases the stability of Adam12 mRNA. We further show that the microRNA-29 family, which has a predicted conserved site in the 3'-untranslated region of mouse Adam12, plays a critical role in mediating the stimulatory effect of Notch on ADAM12 expression. In human cells, Notch up-regulates the expression of the long form, but not the short form, of ADAM12 containing a divergent 3'-untranslated mRNA region. These studies uncover a novel paradigm in Notch signaling and establish Adam12 as a Notch-related gene.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • ADAM Proteins / biosynthesis*
  • ADAM12 Protein
  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Gene Expression Regulation*
  • Humans
  • Membrane Proteins / biosynthesis*
  • Mice
  • MicroRNAs / biosynthesis*
  • Models, Biological
  • NIH 3T3 Cells
  • Peptide Hydrolases / metabolism
  • Receptor, Notch1 / metabolism
  • Receptors, Notch / metabolism*
  • Signal Transduction
  • Up-Regulation


  • 3' Untranslated Regions
  • MIRN29a microRNA, human
  • Membrane Proteins
  • MicroRNAs
  • Notch1 protein, mouse
  • Receptor, Notch1
  • Receptors, Notch
  • Peptide Hydrolases
  • ADAM Proteins
  • ADAM12 Protein
  • ADAM12 protein, human