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PubMed2006

ADAM12 is highly expressed in carcinoma-associated stroma and is required for mouse prostate tumor progression.

The interaction between stromal cells and tumor cells is emerging as a critical aspect of tumor progression. Yet there is a paucity of molecular markers for cells participating in such interactions, and only few genes are known to play a critical role in this process. Here, we describe the identification of ADAM12 (a disintegrin and metalloprotease 12) as a novel marker for a subpopulation of stromal cells that are adjacent to epithelial tumor cells in three mouse carcinoma models (models for prostate, breast and colon cancer). Moreover, we show that ADAM12 is essential for tumor development and progression in the W10 mouse model for prostate cancer. These results suggest that ADAM12 might be a useful marker for stromal cells in mouse tumors that are likely to participate in stromal/tumor cell crosstalk, and that ADAM12 is a potential target for design of drugs that prevent carcinoma growth.

ADAM Proteins↗

PubMed2004

ADAM (a disintegrin and metalloprotease) 12 is expressed in rat and human brain and localized to oligodendrocytes.

ADAM12 is a member of the large family of multidomain metalloprotease-disintegrins which possess cell-binding and metalloprotease properties. Typically, ADAM12 is expressed in mesenchymal cells, developing and regenerating heart and skeletal muscle, bone as well as in certain tumours. This report shows by means of reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry that the protease ADAM12 is detectable in human and rat brain tissue as well as in cultured cells derived from rat brain. With the exception of a very few immunopositive pyramidal neurons in the developing rat brain, the cellular localization of ADAM12 was exclusively confined to oligodendroglial cells. Thus, ADAM12 may be regarded a new suitable marker for this cell type.

ADAM Proteins↗

PubMed2002

ADAM12 alleviates the skeletal muscle pathology in mdx dystrophic mice.

Muscular dystrophy is characterized by muscle degeneration and insufficient regeneration and replacement of muscle fibers by connective tissue. New therapeutic strategies directed toward various forms of muscular dystrophy are needed to preserve muscle mass and promote regeneration. In this study we examined the role of the transmembrane ADAM12, a disintegrin and metalloprotease, which is normally associated with development and regeneration of skeletal muscle. We demonstrate that ADAM12 overexpression in the dystrophin-deficient mdx mice alleviated the muscle pathology in these animals, as evidenced by less muscle cell necrosis and inflammation, lower levels of serum creatine kinase, and less uptake of Evans Blue dye into muscle fibers. These studies demonstrate that ADAM12 directly or indirectly contributes to muscle cell regeneration, stability, and survival.

ADAM Proteins↗

PubMed2005

A role for ADAM12 in breast tumor progression and stromal cell apoptosis.

As in developmental and regenerative processes, cell survival is of fundamental importance in cancer. Thus, a tremendous effort has been devoted to dissecting the molecular mechanisms involved in understanding the resistance of tumor cells to programmed cell death. Recently, the importance of stromal fibroblasts in tumor initiation and progression has been elucidated. Here, we show that stromal cell apoptosis occurs in human breast carcinoma but is only rarely seen in nonmalignant breast lesions. Furthermore, we show that ADAM12, a disintegrin and metalloprotease up-regulated in human breast cancer, accelerates tumor progression in a mouse breast cancer model. ADAM12 does not influence tumor cell proliferation but rather confers both decreased tumor cell apoptosis and increased stromal cell apoptosis. This dual role of ADAM12 in governing cell survival is underscored by the finding that ADAM12 increases the apoptotic sensitivity of nonneoplastic cells in vitro while rendering tumor cells more resistant to apoptosis. Together, these results show that the ability of ADAM12 to influence apoptosis may contribute to tumor progression.

3T3-L1 Cells↗

PubMed2006

ADAM12-S stimulates bone growth in transgenic mice by modulating chondrocyte proliferation and maturation.

UNLABELLED: ADAM12-S transgenic mice exhibit a pronounced increase in the length of bones, such as femur, tibia, and vertebrae. The effect of ADAM12-S on longitudinal bone growth involves the modulation of chondrocyte proliferation and maturation, likely through proteolytic activities and altered cell-extracellular matrix interactions in the growth plate. INTRODUCTION: The disintegrin and metalloprotease ADAM12 is expressed in both osteoblasts and osteoclasts, suggesting a regulatory role of ADAM12 in bone. However, thus far, no in vivo function of ADAM12 in the skeleton has been reported. MATERIALS AND METHODS: Transgenic mice expressing the secreted form of human ADAM12, ADAM12-S, or a truncated metalloprotease-deficient form of ADAM12-S in the circulation were used to study the effects of ADAM12 on the skeleton. In addition, murine chondrocyte cultures were used to study the effect of ADAM12-S on cell-extracellular matrix interactions. RESULTS: ADAM12-S transgenic mice exhibit increased longitudinal bone growth. The increased bone length is progressive and age dependent, with a maximum increase of 17% seen in the femur from 6-month-old transgenic mice. The effect is gene dose dependent, being more pronounced in mice expressing higher levels of the transgene than in a lower-expressing line. Histological analysis revealed no alterations in the growth plate organization, but mean growth plate width was increased. Both the cellular incorporation of bromodeoxyuridine and the width of the collagen type X-positive hypertrophic zone were increased in the growth plate of ADAM12-S transgenic mice. Importantly, mice expressing a truncated form of ADAM12-S that lacked the pro- and metalloprotease domains showed no alterations in bone length, suggesting that protease activity is required for the ADAM12-S effect. In vitro studies showed that ADAM12-S inhibits chondrocyte adhesion to fibronectin and collagen type II. CONCLUSIONS: ADAM12-S stimulates bone growth in mice by modulating chondrocyte proliferation and maturation through mechanisms probably involving both metalloprotease and adhesion activities.

ADAM Proteins↗

PubMed2004

ADAM12 and alpha9beta1 integrin are instrumental in human myogenic cell differentiation.

Knowledge on molecular systems involved in myogenic precursor cell (mpc) fusion into myotubes is fragmentary. Previous studies have implicated the a disintegrin and metalloproteinase (ADAM) family in most mammalian cell fusion processes. ADAM12 is likely involved in fusion of murine mpc and human rhabdomyosarcoma cells, but it requires yet unknown molecular partners to launch myogenic cell fusion. ADAM12 was shown able to mediate cell-to-cell attachment through binding alpha9beta1 integrin. We report that normal human mpc express both ADAM12 and alpha9beta1 integrin during their differentiation. Expression of alpha9 parallels that of ADAM12 and culminates at time of fusion. alpha9 and ADAM12 coimmunoprecipitate and participate to mpc adhesion. Inhibition of ADAM12/alpha9beta1 integrin interplay, by either ADAM12 antisense oligonucleotides or blocking antibody to alpha9beta1, inhibited overall mpc fusion by 47-48%, with combination of both strategies increasing inhibition up to 62%. By contrast with blockade of vascular cell adhesion molecule-1/alpha4beta1, which also reduced fusion, exposure to ADAM12 antisense oligonucleotides or anti-alpha9beta1 antibody did not induce detachment of mpc from extracellular matrix, suggesting specific involvement of ADAM12-alpha9beta1 interaction in the fusion process. Evaluation of the fusion rate with regard to the size of myotubes showed that both ADAM12 antisense oligonucleotides and alpha9beta1 blockade inhibited more importantly formation of large (> or =5 nuclei) myotubes than that of small (2-4 nuclei) myotubes. We conclude that both ADAM12 and alpha9beta1 integrin are expressed during postnatal human myogenic differentiation and that their interaction is mainly operative in nascent myotube growth.

ADAM Proteins↗

PubMed2004

Structure-based virtual screening and biological evaluation of potent and selective ADAM12 inhibitors.

We describe a series of potent and selective inhibitors of ADAM12 that were discovered using computational screening of a focused virtual library. The initial structure-based virtual screening selected 64 compounds from a 3D database of 67,062 molecules. Being evaluated by a cell-based ADAM12 activity assay, compounds 5, 11, 14, 16 were further identified as the potent and selective inhibitors of ADAM12 with low nanomolar IC50 values. The mechanism underlying the potency and selectivity of a representative compound, 5, was investigated through molecular docking studies.

ADAM Proteins↗

PubMed2005

ADAM12-mediated focal adhesion formation is differently regulated by beta1 and beta3 integrins.

ADAM12, adisintegrin and metalloprotease, has been demonstrated to be upregulated in human malignant tumors and to accelerate the malignant phenotype in a mouse model for breast cancer. ADAM12 is a substrate for beta1 integrins and may affect tumor and stromal cell behavior through its binding to beta1 integrins. Here, we report that cells deficient in beta1 integrin or overexpressing beta3 integrin can bind to recombinant full-length human ADAM12 via beta3 integrin. Furthermore, cell binding to ADAM12 via beta3 integrin results in the formation of focal adhesions, which are not formed upon beta1 integrin-mediated cell attachment. We also show that RhoA is involved in beta3 integrin-mediated focal adhesion formation.

ADAM Proteins↗

PubMed2005

Selective modulation of integrin-mediated cell migration by distinct ADAM family members.

A disintegrin and a metalloprotease (ADAM) family members have been implicated in many biological processes. Although it is recognized that recombinant ADAM disintegrin domains can interact with integrins, little is known about ADAM-integrin interactions in cellular context. Here, we tested whether ADAMs can selectively regulate integrin-mediated cell migration. ADAMs were expressed in Chinese hamster ovary cells that express defined integrins (alpha4beta1, alpha5beta1, or both), and cell migration on full-length fibronectin or on its alpha4beta1 or alpha5beta1 binding fragments was studied. We found that ADAMs inhibit integrin-mediated cell migration in patterns dictated by the integrin binding profiles of their isolated disintegrin domains. ADAM12 inhibited cell migration mediated by the alpha4beta1 but not the alpha5beta1 integrin. ADAM17 had the reciprocal effect; it inhibited alpha5beta1- but not alpha4beta1-mediated cell migration. ADAM19 and ADAM33 inhibited migration mediated by both alpha4beta1 and alpha5beta1 integrins. A point mutation in the ADAM12 disintegrin loop partially reduced the inhibitory effect of ADAM12 on cell migration on the alpha4beta1 binding fragment of fibronectin, whereas mutations that block metalloprotease activity had no effect. Our results indicate that distinct ADAMs can modulate cell migration mediated by specific integrins in a pattern dictated, at least in part, by their disintegrin domains.

ADAM Proteins↗

PubMed2003

ADAM12 induces actin cytoskeleton and extracellular matrix reorganization during early adipocyte differentiation by regulating beta1 integrin function.

Changes in cell shape are a morphological hallmark of differentiation. In this study we report that the expression of ADAM12, a disintegrin and metalloprotease, dramatically affects cell morphology in preadipocytes, changing them from a flattened, fibroblastic appearance to a more rounded shape. We showed that the highest levels of ADAM12 mRNA were detected in preadipocytes at the critical stage when preadipocytes become permissive for adipogenic differentiation. Furthermore, as assessed by immunostaining, ADAM12 was transiently expressed at the cell surface concomitant with the reduced activity of beta1 integrin. Co-immunoprecipitation studies indicated the formation of ADAM12/beta1 integrin complexes in these preadipocytes. Overexpression of ADAM12 at the cell surface of 3T3-L1 preadipocytes achieved by transient transfection or retroviral transduction led to the disappearance of the extensive network of actin stress fibers that are characteristic of these cells, and its reorganization into a cortical network located beneath the cell membrane. The cells became more rounded, exhibited fewer vinculin-positive focal adhesions, and adhered less efficiently to fibronectin in attachment assays. Moreover, ADAM12-expressing cells were more prone to apoptosis, which could be prevented by treating the cells with beta1-activating antibodies. A reduced and re-organized fibronectin-rich extracellular matrix accompanied these changes. In addition, beta1 integrin was more readily extracted with Triton X-100 from cells overexpressing ADAM12 than from control cells. Collectively, these results show that surface expression of ADAM12 impairs the function of beta1 integrins and, consequently, alters the organization of the actin cytoskeleton and extracellular matrix. These events may be necessary for early adipocyte differentiation.

ADAM Proteins↗

PubMed2006

Maternal serum ADAM12 levels in Down and Edwards' syndrome pregnancies at 9-12 weeks' gestation.

BACKGROUND: Maternal serum ADAM12 is reduced, on average, in early first-trimester Down and Edwards' syndrome pregnancies but the extent of reduction declines with gestation. Here we study levels at 9-12 weeks when the marker might be used concurrently with other established markers. METHODS: Samples from 16 Down and 2 Edwards' syndrome cases were retrieved from storage and tested together with 313 unaffected singleton pregnancies using a semi-automated time-resolved immuno-fluorometric assay. Results were expressed in multiples of the gestation-specific median (MoM) based on regression. RESULTS: The median in Down syndrome was 0.94 MoM with a 10th-90th centile range of 0.22-1.63 MoM compared with 1.00 and 0.33-2.24 MoM in unaffected controls (P = 0.21, one-side Wilcoxon Rank Sum Test). The two Edwards' syndrome cases had values 0.31 and 2.17 MoM. CONCLUSIONS: ADAM12 cannot be used concurrently with other markers in the late first trimester. However, it does have the potential to be used earlier in pregnancy either concurrently with other early markers or in a sequential or contingent protocol. More data will be required to reliably predict the performance of either approach.

ADAM Proteins↗

PubMed2005

The disintegrin-metalloproteinases ADAM9, ADAM12, and ADAM15 are upregulated in gastric cancer.

The ADAMs (A disintegrin and metalloproteinase) are a family of cell-surface membrane glycoproteins, whose multidomain structure enables diverse roles in a wide range of cellular processes. Accumulating evidence associates an increased expression of individual ADAM family members with various types of cancer, and we investigated the possible involvement of ADAM9, 12 and 15 in the pathogenesis of gastric cancer (GC). Using immunohistochemistry and quantitative RT-PCR, we examined the transcription and expression pattern of ADAM9, 12, and 15 in GCs and the corresponding non-tumor tissue, and in GC cell lines (AGS, MKN45, MKN28, NCI-N87, KATOIII). All three ADAMs were found to be significantly upregulated in GC compared to non-neoplastic foveolar epithelium, with ADAM12 expression being higher in intestinal- than in diffuse-type tumors. In vitro proliferation assays were used to evaluate the effects of ADAM-specific antibodies on the growth of GC cell lines. The administration of anti-ADAM9 and anti-ADAM15 antibodies inhibited cell growth, whereas anti-ADAM12 enhanced the proliferation of the GC cell lines. ADAM9, 12 and 15 are implicated in the malignant growth of GC cells, perhaps via the interaction with adhesion molecules, or the proteolytic 'shedding' of signaling molecules and the consequent transactivation of their receptors, such as the epithelial growth factor receptor and its ligands. The resultant modulation of the tumor-host interface may contribute to the pathogenesis, development or progression of gastric cancer.

ADAM Proteins↗

PubMed2003

Compensation for dystrophin-deficiency: ADAM12 overexpression in skeletal muscle results in increased alpha 7 integrin, utrophin and associated glycoproteins.

Mouse models for genetic diseases are among the most powerful tools available for developing and testing new treatment strategies. ADAM12 is a disintegrin and metalloprotease, previously demonstrated to significantly alleviate the pathology of mdx mice, a model for Duchenne muscular dystrophy in humans. More specifically ADAM12 appeared to prevent muscle cell necrosis in the mdx mice as evidenced by morphological analysis and by the reduced levels of serum creatine kinase. In the present study we demonstrated that ADAM12 may compensate for the dystrophin deficiency in mdx mice by increasing the expression and redistribution of several components of the muscle cell-adhesion complexes. First, we analyzed transgenic mice that overexpress ADAM12 and found mild myopathic changes and accelerated regeneration following acute injury. We then analyzed changes in gene-expression profiles in mdx/ADAM12 transgenic mice compared with their littermate controls and found only a few genes with an expression change greater than 2-fold between mdx/ADAM12 and mdx. The small changes in gene expression were unexpected, considering the marked improvement of the mdx pathology when ADAM12 is overexpressed, and suggested that significant changes in mdx/ADAM12 muscle might occur post-transcriptionally. Indeed, by immunostaining and immunoblotting we found an approximately 2-fold increase in expression, and distinct extrasynaptic localization, of alpha 7B integrin and utrophin, the functional homolog of dystrophin. The expression of the dystrophin-associated glycoproteins was also increased. In conclusion, these results demonstrate a novel way to alleviate dystrophin deficiency in mice, and may stimulate the development of new approaches to compensate for dystrophin deficiency in animals and humans.

ADAM Proteins↗

PubMed2005

Role of meltrin {alpha} (ADAM12) in obesity induced by high- fat diet.

Meltrin alpha is a member of the metalloprotease-disintegrin (ADAM) family. In this paper we demonstrate that meltrin alpha is involved in the development of white adipose tissue. Compared with wild-type mice, meltrin alpha(-/-) mice displayed moderate resistance to weight gain induced by a high-fat diet, mainly because of an impaired increase in the number of adipocytes. There was no obvious difference in adipocyte size between wild-type and meltrin alpha(-/-) mice, suggesting normal maturation of adipocytes of the latter under a high-fat diet. Embryonic fibroblasts and stromal-vascular cells lacking meltrin alpha exhibited impaired cell proliferation upon adipogenic stimulation, which was accompanied by moderate defects in adipose differentiation. Addition of culture medium conditioned with wild-type cells in an early phase of adipose differentiation did not restore the defects in the meltrin alpha(-/-) cells. These results uncover the involvement of meltrin alpha in the development of obesity and in adipogenic cell proliferation.

ADAM Proteins↗

PubMed2003

Phenotypic analysis of Meltrin alpha (ADAM12)-deficient mice: involvement of Meltrin alpha in adipogenesis and myogenesis.

Meltrin alpha (ADAM12) is a metalloprotease-disintegrin whose specific expression patterns during development suggest that it is involved in myogenesis and the development of other organs. To determine the roles Meltrin alpha plays in vivo, we generated Meltrin alpha-deficient mice by gene targeting. Although the number of homozygous embryos are close to the expected Mendelian ratio at embryonic days 17 to 18, ca. 30% of the null pups born die before weaning, mostly within 1 week of birth. The viable homozygous mutants appear normal and are fertile. Most of the muscles in the homozygous mutants appear normal, and regeneration in experimentally damaged skeletal muscle is unimpeded. In some Meltrin alpha-deficient pups, the interscapular brown adipose tissue is reduced, although the penetrance of this phenotype is low. Impaired formation of the neck and interscapular muscles is also seen in some homozygotes. These observations suggest Meltrin alpha may be involved in regulating adipogenesis and myogenesis through a linked developmental pathway. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a candidate substrate of Meltrin alpha, and we found that TPA (12-O-tetradecanoylphorbol-13-acetate)-induced ectodomain shedding of HB-EGF is markedly reduced in embryonic fibroblasts prepared from Meltrin alpha-deficient mice. We also report here the chromosomal locations of Meltrin alpha in the mouse and rat.

ADAM Proteins↗

PubMed2004

Regulation of ADAM12 cell-surface expression by protein kinase C epsilon.

The ADAM (a disintegrin and metalloprotease) family consists of multidomain cell-surface proteins that have a major impact on cell behavior. These transmembrane-anchored proteins are synthesized as proforms that have (from the N terminus): a prodomain; a metalloprotease-, disintegrin-like-, cysteine-rich, epidermal growth factor-like, and transmembrane domain; and a cytoplasmic tail. The 90-kDa mature form of human ADAM12 is generated in the trans-Golgi through cleavage of the prodomain by a furin-peptidase and is stored intracellularly until translocation to the cell surface as a constitutively active protein. However, little is known about the regulation of ADAM12 cell-surface translocation. Here, we used human RD rhabdomyosarcoma cells, which express ADAM12 at the cell surface, in a temporal pattern. We report that protein kinase C (PKC) epsilon induces ADAM12 translocation to the cell surface and that catalytic activity of PKCepsilon is required for this translocation. The following results support this conclusion: 1) treatment of cells with 0.1 microM phorbol 12-myristate 13-acetate (PMA) enhanced ADAM12 cell-surface immunostaining, 2) ADAM12 and PKCepsilon could be co-immunoprecipitated from membrane-enriched fractions of PMA-treated cells, 3) RD cells transfected with EGFP-tagged, myristoylated PKCepsilon expressed more ADAM12 at the cell surface than did non-transfected cells, and 4) RD cells transfected with a kinase-inactive PKCepsilon mutant did not exhibit ADAM12 cell-surface translocation upon PMA treatment. Finally, we demonstrate that the C1 and C2 domains of PKCepsilon both contain a binding site for ADAM12. These studies show that PKCepsilon plays a critical role in the regulation of ADAM12 cell-surface expression.

ADAM Proteins↗

PubMed2026

miR-2116-5p functions as a tumor suppressor in lung adenocarcinoma by targeting ADAM12 and serves as a prognostic biomarker.

BACKGROUND: MicroRNAs play key roles in tumor progression. miR-2116-5p is downregulated in lung adenocarcinoma (LUAD), and this study investigated its prognostic value and functional role in the disease. MATERIALS AND METHODS: A total of 125 LUAD patients contributed tissue samples. miR-2116-5p and ADAM12 expression in tissues and cell lines were detected by RT‑qPCR. Clinicopathological correlations of miR-2116-5p were analyzed using the chi-square test. Kaplan‑Meier and Cox regression were employed to assess prognostic significance. CCK‑8, Transwell, and dual‑luciferase reporter assays were performed to investigate miR‑2116-5p function and its targeting of ADAM12. Rescue experiments validated the functional involvement of ADAM12. RESULTS: Significant downregulation of miR-2116-5p was observed in LUAD tissues and cell lines. Low expression was markedly linked to lymph node metastasis (P = 0.013) and advanced TNM stage (P = 0.002). Patients exhibiting reduced miR-2116-5p levels showed worse overall survival, and it was identified as an independent prognostic factor (HR = 2.521, 95% CI: 1.129-5.628, P = 0.020). Functional experiments showed that increasing miR-2116-5p expression suppressed LUAD cell proliferation, migration, and invasion, whereas its knockdown promoted these processes. ADAM12 was confirmed as a direct target, with expression inversely correlated in LUAD tissues (r = -0.749, P < 0.001). ADAM12 overexpression effectively counteracted the ability of miR-2116-5p to suppress proliferation, migration, and invasion. CONCLUSION: miR‑2116-5p suppresses LUAD progression by targeting ADAM12, suggesting it may serve as a prognostic biomarker and therapeutic target.

Humans↗

PubMed2005

Cooperation of the metalloprotease, disintegrin, and cysteine-rich domains of ADAM12 during inhibition of myogenic differentiation.

The extracellular domain of the mature form of ADAM12 consists of the metalloprotease, disintegrin, cysteine-rich, and epidermal growth factor (EGF)-like domains. The disintegrin, cysteine-rich, and EGF-like fragments have been shown previously to support cell adhesion via activated integrins or proteoglycans. In this study, we report that the entire extracellular domain of mouse ADAM12 produced in Drosophila S2 cells supported efficient adhesion and spreading of C2C12 myoblasts even in the absence of exogenous integrin activators. This adhesion was not mediated by beta1 integrins or proteoglycans, was myoblast-specific, and required the presence of both the metalloprotease and disintegrin/cysteine-rich domains of ADAM12. Analysis of the recombinant proteins by far-UV circular dichroism suggested that the secondary structures of the autonomously expressed metalloprotease domain and the disintegrin/cysteine-rich/EGF-like domains differ from the structures present in the intact extracellular domain. Furthermore, the intact extracellular domain (but not the metalloprotease domain or the disintegrin/cysteine-rich/EGF-like fragment alone) decreased the expression of the cell cycle inhibitor p21 and myogenin, two markers of differentiation, and inhibited C2C12 myoblast fusion. Thus, the novel protein-protein interaction reported here involving the extracellular domain of ADAM12 may have important biological consequences during myoblast differentiation.

3T3 Cells↗