The Role of SnoN in Transforming Growth Factor β1 induced Expression of Metalloprotease- Disintegrin ADAM12

Increased expression of metalloprotease-disintegrin ADAM12 is a hallmark of several pathological conditions, including cancer, cardiovascular disease, and certain inflammatory diseases of the central nervous system or the muscoskeletal system. We show that transforming growth factor beta 1 (TGF beta 1) is a potent inducer of ADAM12 mRNA and protein in mouse fibroblasts and in mouse and human mammary epithelial cells. Induction of ADAM12 is detected within 2 h of treatment with TGF beta 1, is Smad2/Smad3-dependent, and is a result of derepression of the Adam12 gene. SnoN, a negative regulator of the TGF beta signaling pathway, is a master regulator of ADAM12 expression in response to TGF beta 1 stimulation. Overexpression of SnoN in NIH3T3 cells reduces the magnitude of ADAM12 induction by TGF beta 1 treatment. Down-regulation of SnoN expression by short hairpin RNA enhances TGF beta 1-induced expression of ADAM12. In a panel of TGF beta 1-responsive cancer cell lines with high expression of SnoN, induction of ADAM12 by TGF beta 1 is significantly impaired, suggesting that the endogenous SnoN plays a role in regulating ADAM12 expression in response to TGF beta 1. Identification of SnoN as a repressor of the ADAM12 gene should contribute to advances in the studies on the role of ADAM12 in tumor progression and in the development of other pathologies.