Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cytokine transforming growth factor-beta (TGF-beta) has multiple effects on a wide variety of cell types. These effects include modulation of growth and regulation of gene transcription. In a few instances, TGF-beta has also been shown to regulate gene expression posttranscriptionally by altering message stability, but the pathway by which this activity is executed remains largely unknown. In the present work, we demonstrate that TGF-beta 1 has no effect on transcription of the elastin gene in cultured human fetal lung fibroblasts, but does stabilize elastin messenger RNA (mRNA), leading to a dramatic increase in the steady-state level of elastin mRNA. A corresponding increase in production of tropoelastin accompanies the increase in elastin mRNA. Through the use of specific inhibitors, we demonstrate that phosphatidylcholine (PC)-specific phospholipase C (PLC) and protein kinase C (PKC) are involved in mediating the elastin message stabilization. In contrast, G proteins and extracellularly regulated kinases do not appear to be involved. These results suggest that although the TGF-beta signaling pathway leading to message stabilization shares components with that modulating transcription, the message-stabilization pathway also contains diverse other elements.
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PMID:Stabilization of elastin mRNA by TGF-beta: initial characterization of signaling pathway. 922 2

The TGF-betas are multipotent in their biological activity, modulating cell growth and differentiation as well as extracellular matrix deposition and degradation. Most of these activities involve modulation of gene transcription. However, TGF-beta1 has been shown previously to substantially increase the expression of elastin by stabilization of tropoelastin mRNA through a signaling pathway which involves a phosphatidylcholine-specific phospholipase and a protein kinase C. The present results, through the use of specific inhibitors of geranylgeranyl transferase I, farnesyl transferase, and acyl transferase, demonstrate that geranylgeranylated and acylated, but not farnesyslated protein(s) is required for this TGF-beta1 effect. In addition, the general tyrosine kinase inhibitor genistein completely blocked this TGF-beta1 effect. The results suggest that the TGF-beta1 signaling pathway requires not only receptor ser/thr kinase activity, but also tyrosine kinase and small GTPase activities.
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PMID:Requirement for geranylgeranyl transferase I and acyl transferase in the TGF-beta-stimulated pathway leading to elastin mRNA stabilization. 981 54

The cytokine transforming growth factor-beta has multiple effects on a wide variety of cell types. These effects include modulation of growth and regulation of gene transcription. In the present work, we demonstrate that TGF-beta1 increases transcription of the latent transforming growth factor-beta binding protein-2 ( LTBP-2) gene in cultured human fetal lung fibroblasts leading to a significant increase in LTBP-2 mRNA steady state level. The stability of LTBP-2 mRNA was not appreciably altered. A corresponding increase in production of LTBP-2 protein accompanied the increase in mRNA. Through the use of specific inhibitors, we demonstrate that a member of the Ras super family and a protein kinase C, probably of the atypical (non-diacylglycerol, non-Ca++ dependent) class are likely to be components in the signaling pathway. However, phospholipases, G proteins and extracellular-signal regulated kinases do not appear to be involved. These results combined with previous findings on elastin regulation by TGF-beta1 (Kucich et al. (1997). Am. J. Respir. Cell Mol. Biol., 17: 10-16) demonstrate that TGF-beta1 can coordinately increase the steady state levels of mRNAs encoding components of the elastic fiber, but through diverse mechanisms. In contrast to LTBP-2, increased elastin expression is achieved by message stabilization. Furthermore, the TGF-beta1 signaling pathways differ and while the pathway leading to increased LTBP-2 transcription shares components with those modulating transcription of other genes, it is unlikely to be precisely congruent with any other previously described one.
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PMID:Signaling pathway by which TGF-beta1 increases expression of latent TGF-beta binding protein-2 at the transcriptional level. 986 26

We have established that treatment of cultured human skin fibroblasts with tropoelastin or with heterogenic peptides, obtained after organo-alkaline or leukocyte elastase hydrolysis of insoluble elastin, induces a high expression of pro-collagenase-1 (pro-matrix metalloproteinase-1 (pro-MMP-1)). The identical effect was achieved after stimulation with a VGVAPG synthetic peptide, reflecting the elastin-derived domain known to bind to the 67-kDa elastin-binding protein. This clearly indicated involvement of this receptor in the described phenomenon. This notion was further reinforced by the fact that elastin peptides-dependent MMP-1 up-regulation has not been demonstrated in cultures preincubated with 1 mm lactose, which causes shedding of the elastin-binding protein and with pertussis toxin, which blocks the elastin-binding protein-dependent signaling pathway involving G protein, phospholipase C, and protein kinase C. Moreover, we demonstrated that diverse peptides maintaining GXXPG sequences can also induce similar cellular effects as a "principal" VGVAPG ligand of the elastin receptor. Results of our biophysical studies suggest that this peculiar consensus sequence stabilizes a type VIII beta-turn in several similar, but not identical, peptides that maintain a sufficient conformation to be recognized by the elastin receptor. We have also established that GXXPG elastin-derived peptides, in addition to pro-MMP-1, cause up-regulation of pro-matrix metalloproteinase-3 (pro-stromelysin 1). Furthermore, we found that the presence of plasmin in the culture medium activated these MMP proenzymes, leading to a consequent degradation of collagen substrate. Our results may be, therefore, relevant to pathobiology of inflammation, in which elastin-derived peptides bearing the GXXPG conformation (created after leukocyte-dependent proteolysis) bind to the elastin receptor of local fibroblasts and trigger signals leading to expression and activation of MMP-1 and MMP-3, which in turn exacerbate local connective tissue damage.
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PMID:Conformational dependence of collagenase (matrix metalloproteinase-1) up-regulation by elastin peptides in cultured fibroblasts. 1108 20

With aging we assist to alterations in the vascular structure and function. One important factor in these vascular wall changes is the degradation of the elastin fibre major protein: elastin. Elastin peptides derived from the degradation are present in human sera. Elastin peptides induce on fibroblasts, phagocytic cells, lymphocytes, smooth muscle cells and endothelial cells, a variety of biological effects mediated by the elastin-laminin receptor which has been demonstrated to be present on the membrane of these cells. The transduction pathway of the ELR receptor involves the activation of phospholipase C (PLC) by a pertussis toxin sensitive G-protein. PLC induces the production of inositol trisphosphate (IP3) leading to the increase of the intracellular free calcium on one hand, and of diacylglycerol (DAG) which stimulates the translocation to the membrane of PKC leading to the phosphorylation of members of the MAPK family, such as p42/p44 MAPK. A progressive age dependent uncoupling of the elastin-laminin receptor occurs impairing its transduction pathway and which results in alteration of the calcium signaling and loss in calcium homeostasis of the cells. These alterations in the signal transduction of the elastin-laminin receptor result in modified activities of parenchymal and phagocytic cells with aging, such as free radical production and elastase release. Thus, these age-related alterations in the elastin-laminin receptor signal transduction may be involved in the atherogenesis.
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PMID:Age-related alterations in the signal transduction pathways of the elastin-laminin receptor. 1142 70

Elastin is a major component of the extracellular matrix. Elastin peptides derived from its degradation are present in human sera. Elastin peptides induce on fibroblasts, phagocytic cells, lymphocytes, smooth muscle cells and endothelial cells, a variety of biological effects mediated by the elastin-laminin receptor which has been demonstrated to be present on the membrane of these cells. The transduction pathway of the ELR receptor involves the activation of phospholipase C (PLC) by a pertussis toxin sensitive G-protein. PLC induces the production of inositol trisphosphate (IP3) leading to the increase of the intracellular free calcium on one hand, and of diacylglycerol (DAG) which stimulates the translocation to the membrane of PKC leading to the phosphorylation of members of the MAPK family, such as p42/p44 MAPK. Considering the multiple biological effects of ELR the elucidation of the complexity of the signaling pathways will help to better modulate it, mainly in pathological situations such as atherosclerosis.
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PMID:[The elastin-laminin receptor]. 1172 28

Soluble elastin-derived peptides from alkaline or elastase hydrolysis of insoluble elastin, as well as tropoelastin, increase matrix metalloproteinase-2 (MMP-2) production by human skin fibroblasts in culture as determined by gelatin zymography and ELISA. Such an effect is time and concentration dependent; it can be reproduced by synthetic elastin: VGVAPG, PGAIPG, and laminin: LGTIPG, hexapeptides and inhibited by lactose and is therefore elastin receptor-mediated. The steady state levels of MMP-2 mRNAs are invariant following elastin-fibroblasts interaction. Inhibition of phospholipase C (D-609), ADP-ribosylation factor (brefeldin), protein kinase C (RO-318220) and phospholipase D (1-propanol) totally abolished the elastin-mediated increase of MMP-2 production. It suggested that the post-transcriptional mechanism controlling the elastin-mediated overproduction of MMP-2 involved a cascade leading to phospholipase D activation.
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PMID:[Effect of elastin peptides on the production of matrix metalloproteinase 2 by human skin fibroblasts in culture]. 1172 29

Transforming growth factors (TGFs)-beta are multipotent in their biologic activity, regulating cell growth and differentiation as well as extracellular matrix deposition and degradation. Most of these activities involve modulation of gene transcription, but TGF-beta1 has been shown previously to substantially increase the expression of elastin by stabilization of tropoelastin mRNA through a signaling pathway that likely involves a phosphatidylcholine-specific phospholipase C, a protein kinase C, prenylated and acylated protein(s), and one or more tyrosine kinases. However, there is a 4- to 6-h lag period after the addition of TGF-beta1 before significant stimulation of elastin expression is observed and the question of whether the Smads are involved has not been addressed. In the present work, using cultured human fetal lung fibroblasts, we show through the use of specific inhibitors and transfection of a Smad 7 construct that in addition to de novo protein synthesis and active Smads, the extended activity of protein kinase C (PKC)-delta and the stress-activated protein kinase, p38, is required for TGF-beta1 to achieve elastin mRNA stabilization.
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PMID:Transforming growth factor-beta stabilizes elastin mRNA by a pathway requiring active Smads, protein kinase C-delta, and p38. 1180 64

Recent studies have demonstrated that H(2)O(2) acts as a second messenger of mitogenic signaling and that catalase is under the regulation of PKA and PKC signaling. Here we examined whether catalase binds any mitogenic signaling molecules. Our results indicated that serum stimulation of HeLa, Caco-2, and LiSa-2 cells, but not BJ-1 and primary human bronchial epithelial cells, resulted in catalase binding to Grb2. Whereas serum deprivation, butyrate, and herbimycin-A negatively regulated the binding, an extended culture of confluent Caco-2 cells resulted in binding of an additional but as yet unidentified molecule to the Grb2-catalase complex. Expression of active catalase nearly 15-fold over control level in Tet-off HeLa cells substantially increased binding to Grb2, and this was sensitive to 3-aminotriazole, a specific catalase inhibitor. Furthermore, fibrinogen, fibronectin, and laminin, but not collagen types I to V, hyaluronic acid, elastin, insulin, EGF, IGF-I, PDGF, or NGF, resulted in binding similar to that of serum. A mutation of tyrosine to phenylalanine at 447 abolished the binding capability of catalase to Grb2 in vitro. These results support the view that catalase (447)Tyr-Val-Asn-Val binds Grb2 upon phosphorylation in tumor cells when stimulated with serum or ligands for integrin receptors. This is the first report demonstrating that catalase binds a SH2 domain of the molecule and participates in integrin signaling.
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PMID:Catalase binds Grb2 in tumor cells when stimulated with serum or ligands for integrin receptors. 1518 56

Pleiotrophin (PTN, Ptn) is an 18-kDa secretory cytokine expressed in many breast cancers; however, the significance of Ptn expression in breast cancer has not been established. We have now tested three models to determine the role of inappropriate expression of Ptn in breast cancer. Mouse mammary tumor virus (MMTV) promoter-driven Ptn expressed in MMTV-polyoma virus middle T antigen (PyMT)-Ptn mouse breast cancers was first shown to induce rapid growth of morphologically identified foci of "scirrhous" carcinoma and to extensively remodel the microenvironment, including increased tumor angiogenesis and striking increases in mouse protocollagens Ialpha2, IValpha5, and XIalpha1, and elastin. Ectopic Ptn expression in MCF-7 (human breast cancer)-Ptn cell xenografts also was shown to markedly increase MCF-7-Ptn cell xenograft growth in nude mice; furthermore, it induced extensive remodeling of the microenvironment and tumor angiogenesis. In a coculture model of equal numbers of NIH 3T3 stromal fibroblasts and MCF-7-Ptn cells, PTN secreted from MCF-7-Ptn cells was then shown to induce a more malignant MCF-7-Ptn breast cancer cell phenotype and extensive remodeling of the MCF-7-Ptn/NIH 3T3 cell microenvironment; it up-regulated expression of markers of aggressive breast cancers, including PKCdelta and matrix metalloproteinase-9 in both MCF-7-Ptn and NIH 3T3 cells. The morphological phenotypes of MCF-7-Ptn cell xenografts and MCF-7-Ptn cell/NIH 3T3 cell cocultures closely resembled breast cancers in MMTV-PyMT-Ptn mice. Inappropriate expression of Ptn thus promotes breast cancer progression in mice; the data suggest that secretion of PTN through stimulation of the stromal cell microenvironment alone may be sufficient to account for significant features of breast cancer progression.
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PMID:Secretion of pleiotrophin stimulates breast cancer progression through remodeling of the tumor microenvironment. 1757 9


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