title: Metalloprotease-disintegrin ADAM12 expression is regulated by Notch signaling via microRNA-29.
abstract: 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.
authors.affiliation: Department of Biochemistry, Kansas State University, Manhattan, Kansas 66506, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Emilia
authors.initials: E
authors.lastname: Solomon
authors.forename: Sara
authors.initials: S
authors.lastname: Duhachek Muggy
authors.forename: Danqiong
authors.initials: D
authors.lastname: Sun
authors.forename: Anna
authors.initials: A
authors.lastname: Zolkiewska
mesh_terms: D020413:3' Untranslated Regions; D051722:ADAM Proteins / Q000096:biosynthesis*; D000072199:ADAM12 Protein; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis*; D008954:Models, Biological; D041681:NIH 3T3 Cells; D010447:Peptide Hydrolases / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D020413:3' Untranslated Regions; C532045:MIRN29a microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D051880:Receptors, Notch; D010447:Peptide Hydrolases; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human