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

Abstract

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 ␤1 (TGF␤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␤1, is Smad2/Smad3-dependent, and is a result of derepression of the ADAM12, a member of the metalloprotease-disintegrin family of proteins, has been implicated in the progression of cancer, cardiovascular disease, osteoarthritis, and neurological disorders (1). The ADAM12 gene is frequently mutated in human breast cancers (2, 3), and cancer-associated mutations cause mislocalization of the ADAM12 protein in cells and alter its function (4). Missense single nuclear polymorphism in the ADAM12 gene shows strong association with osteoarthritis (5, 6). In addition to changes in its amino acid sequence, expression levels of ADAM12 are significantly increased in many pathological states. For example, ADAM12 expression levels are 20 -30-fold higher in human breast tumors than in normal mammary epithelium (7-12). ADAM12 expression is also markedly up-regulated in cancers of the liver, lung, stomach, colon, prostate, bladder, and in glioblastoma (13-18). Increased ADAM12 expression levels are found in the cardiac tissue of patients with hypertrophic obstructive cardiomyopathy (19) and in mice with angiotensin II-induced hypertension and cardiac hypertrophy (20,21). During inflammatory responses and aseptic osteolysis associated with loosened hip replacement implants, ADAM12 is up-regulated in the interface tissue around loosening implants (22). In experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, ADAM12 level is markedly increased in the T cells that infiltrate spinal cords (23).The mechanisms regulating ADAM12 expression, in particular those that may be responsible for altered levels of ADAM12 in various pathological states, are poorly understood. Previous studies employing hepatic stellate cells, a mesenchymal cell type in hepatic parenchyma, have indicated that ADAM12 expression is induced by transforming growth factor ␤ (TGF␤) 2 (13, 24). The TGF␤ signaling pathway is initiated when one of the family members, e.g. TGF␤1, -␤2, or -␤3, binds to a complex of TGF␤ type I and type II serine/threonine kinase receptors (T␤RI and T␤RII, respectively) and induces phosphorylation and activation of T␤RI by T␤RII. T␤RI then phosphorylates receptor Smads (R-Smads), Smad2 and Smad3. Phosphorylated Smad2/3 associate with the common partner Smad4 and translocate to the nucleus, where they regulate transcription of target genes (25,26). In addition, receptor activation in certain cell types leads to Smad-independent responses via the activation of mitogen-activated protein kinases (MAPKs), phosphoinositide 3-kinase, and Rho family memb...

ADAM12 redistributes and activates MMP-14, resulting in gelatin degradation, reduced apoptosis, and increased tumor growth

“…For this purpose, we used the invasive breast cancer cell line MDA-MB-231, which has been previously shown to express ADAM12 (Solomon et al, 2010). We confirmed that this line had cell surface expression of ADAM12 by cytospin experiments, and furthermore showed the presence of MMP-14 in juxtaposition to ADAM12 at the cell surface (Fig.…”

Metalloprotease-Disintegrin ADAM12 Expression Is Regulated by Notch Signaling via MicroRNA-29

“…We and others have recently demonstrated that ADAM12 expression is induced by transforming growth factor ␤ (TGF␤) via Smad-dependent and Smad-independent signaling pathways (35)(36)(37)(38)(39). Consistently, ADAM12 induction by TGF␤ is significantly attenuated in Smad2 Ϫ/Ϫ or Smad3 Ϫ/Ϫ MEFs (37).…”

“…We have recently reported that inhibition of protein synthesis in NIH3T3 cells with cycloheximide results in a marked elevation of the Adam12 mRNA level (37). As protein turnover rates for IB are much higher than the turnover rates for NFB (44,45), inhibition of the new protein synthesis leads to imbalance between IB and NF-B and preferential accumulation of NF-B.…”

“…5A). We have recently shown that the core Adam12 promoter is located in the Ϫ187/ϩ91 region (37). None of the Adam12 promoter constructs were significantly activated by ectopic expression of NICD1 (Fig.…”

Metalloproteinases in hypertension and cardiac disease: differential expression and mutual regulation

“…These findings suggest a mechanism for ADAM-12 in cardiac fibrosis [32,33]. In addition, TGF-β can induce the expression of ADAM-12, which is mediated by TGF-β's ability to promote the degradation of SnoN, a negative regulator of TGF-β/Smad signaling [34,35].…”