Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

All mammalian cells absolutely require polyamines (putrescine, spermidine, and spermine) for growth. Here we show that the overexpression of cDNA for S-adenosylmethionine decarboxylase (AdoMetDC), the main regulatory enzyme in the biosynthesis of higher polyamines, induces transformation of rodent fibroblasts when expressed in the sense or the antisense orientation. Both transformants were able to induce invasive tumors in nude mice. Neither transformation was associated with activation of the mitogen-activated protein kinases Erk1 and Erk2. Instead, the AdoMet DC sense, but not antisense, transformants displayed constitutive activation of the c-Jun NH(2)-terminal kinase (JNK) pathway. However, both transformations converged on persistent phosphorylation of endogenous c-Jun at Ser73. The phenotype of the AdoMetDC sense transformants was reversed by expression of dominant-negative mutants of SEK1 (MKK4), JNK1, and c-Jun (TAM-67), which were also found to impair cytokinesis. Similarly, TAM-67 reverted the morphology of the AdoMetDC-antisense expressors. This report is the first demonstration of a protein whose overexpression or block of synthesis can induce cell transformation. In addition, we show that the polyamine biosynthetic enzymes require c-Jun activation for eliciting their biological effects.
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PMID:c-Jun activation-dependent tumorigenic transformation induced paradoxically by overexpression or block of S-adenosylmethionine decarboxylase. 1107 65

S-adenosylmethionine decarboxylase (AdoMetDC) is a key enzyme in the synthesis of polyamines essential for cell growth and proliferation. Its overexpression induces the transformation of murine fibroblasts in both sense and antisense orientations, yielding highly invasive tumors in nude mice. These cell lines hence provide a good model to study cell invasion. Here, the gene expression profiles of these cells were compared with their normal counterpart by microarray analyses (Incyte Genomics, Palo Alto, CA, and Affymetrix, Santa Clara, CA). Up-regulation of the actin sequestering molecule thymosin beta4 was the most prominent change in both cell lines. Tetracycline-inducible expression of thymosin beta4 antisense RNA caused a partial reversal of the transformed phenotype. Further, reversal of transformation by dominant-negative mutant of c-Jun (TAM67) caused reduction in thymosin beta4 mRNA. Interestingly, a sponge toxin, latrunculin A, which inhibits the binding of thymosin beta4 to actin, was found to profoundly affect the morphology and proliferation of the AdoMetDC transformants and to block their invasion in three-dimensional Matrigel. Thus, thymosin beta4 is a determinant of AdoMetDC-induced transformed phenotype and invasiveness. Up-regulation of thymosin beta4 was also found in ras-transformed fibroblasts and metastatic human melanoma cells. These data encourage testing latrunculin A-like and other agents interfering with thymosin beta4 for treatment of thymosin beta4-overexpressing tumors with high invasive and metastatic potential.
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PMID:Thymosin beta4 is a determinant of the transformed phenotype and invasiveness of S-adenosylmethionine decarboxylase-transfected fibroblasts. 1642 99

Understanding the mechanisms of tumor cell invasion is essential for our attempts to prevent cancer deaths. We screened by DNAmicroarrays the c-Jun- and transformation-related gene expression changes in S-adenosylmethionine decarboxylase (AdoMetDC)-overexpressing mouse fibroblasts that are highly invasive in vivo, and their derivatives expressing a tetracycline-inducible dominant-negative mutant of c-Jun (TAM67) or c-Jun shRNA. Among the small set of target genes detected were integrins alpha6 and beta7, cathepsin L and thymosin beta4, all upregulated in the AdoMetDC-transformed cells and downregulated upon reversal of transformation by TAM67 or c-Jun shRNA. The upregulation of integrin alpha6 subunit, pairing with integrin beta1, endowed the transformed cells with the capability to attach to basement membrane laminin and to spread. Further, inhibition of integrin alpha6 or beta1 function with neutralizing antibodies blocked the invasiveness of AdoMetDC-transformants and human HT-1080 fibrosarcoma cells in three-dimensional Matrigel. Moreover, immunohistochemical analyses showed strong integrin alpha6 staining in high-grade human fibrosarcomas. Our data show that c-Jun can regulate all three key steps of invasion: cell adhesion (integrin alpha6), basement membrane/extracellular matrix degradation (cathepsin L) and cell migration (thymosin beta4). In addition, this is the first study to associate integrin beta7, known as a leukocyte-specific integrin binding to endothelial/epithelial cell adhesion molecules, with the transformed phenotype in cells of nonleukocyte origin. As tumor cell invasion is a prerequisite for metastasis, the observed critical role of integrin alpha6beta1 in fibrosarcoma cell invasion/spreading allures testing antagonists to integrin alpha6beta1, alone or combined with inhibitors of cathepsin L and thymosin beta4, as chemotherapeutic agents.
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PMID:Identification of integrins alpha6 and beta7 as c-Jun- and transformation-relevant genes in highly invasive fibrosarcoma cells. 1940 19