Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have identified and characterized a calcium-dependent metalloproteinase which is induced in rat pheochromocytoma cells (PC12 cells) during differentiation with nerve growth factor (NGF). Assays of proteolytic activity in media from differentiated PC12 cell cultures revealed a NGF-dependent increase in the activity of a proteinase which has a molecular weight of 62 kDa. Studies using serine, thiol, and metalloproteinase inhibitors demonstrated that the secreted enzyme is a metalloproteinase. Treatment of culture supernatants with aminophenylmercuric acid (APMA), a known activator of metalloproteinases, resulted in a decrease in the molecular weight of the proteinase. Western blot analysis of culture media from NGF-treated PC12 cells using an antibody directed against a synthetic peptide of rat transin identified this metalloproteinase as transin. Treatment of PC12 cells with acidic and basic fibroblast growth factor (FGF) resulted in distinct morphological changes as well as transin release. Incubation with epidermal growth factor (EGF) did not induce transin release. Dexamethasone inhibited the induction of transin release by NGF. 35S-methionine labeling and immunoprecipitation of newly synthesized proteins from culture supernatants confirmed that NGF induced the synthesis of this enzyme 8 hr after NGF treatment. The NGF-dependent induction of transin, a calcium-dependent metalloproteinase which degrades type IV collagen, laminin, and fibronectin suggests that transin may function to degrade the surrounding extracellular matrix during the invasive process of axonal elongation in neuronal development thereby allowing the movement of growth cones and axons toward specific targets.
 ...
PMID:Differentiation of PC12 cells with nerve growth factor is associated with induction of transin synthesis and release. 137 77

To investigate the role of the gp140trk receptor tyrosine kinase in nerve growth factor (NGF)-induced differentiation, we have overexpressed gp140trk in the NGF-responsive PC12 cell line. Here we demonstrate that overexpression of gp140trk results in marked changes in NGF-induced differentiation. Whereas PC12 cells elaborated neurites after 2 days of continuous exposure to NGF, PC12 cells overexpressing gp140trk by 20-fold(trk-PC12) began this process within hours. Compared with wild-type PC12 cells, trk-PC12 exhibited an increase in both high and low affinity NGF-binding sites. Furthermore, trk-PC12 cells displayed an enhanced level of NGF-dependent gp140trk autophosphorylation, and this activity was sustained for many hours following ligand binding. The tyrosine phosphorylation or activity of several cellular proteins, such as PLC-gamma 1, PI-3 kinase, and Erk1 and the expression of the mRNA for the late response gene transin were also sustained as a consequence of gp140trk overexpression. The data indicate that overexpression of gp140trk in PC12 cells markedly accelerates NGF-induced differentiation pathways, possibly through the elevation of gp140trk tyrosine kinase activity.
 ...
PMID:Overexpression of the trk tyrosine kinase rapidly accelerates nerve growth factor-induced differentiation. 138 75

Schwannoma-derived growth factor (SDGF) was initially isolated from schwannoma cells as a mitogen for glial cells and fibroblasts. The present data show that SDGF causes the morphological and molecular differentiation of rat PC12 cells in a manner similar to, but distinguishable from nerve growth factor (NGF). It also promotes PC12 survival in serum-free conditions. SDGF induced changes include neurite outgrowth and the induction of the mRNAs for GAP-43 and transin, proteins which are highly expressed in axons. In addition, both SDGF and NGF induce the transcription factor, NGFI-A. The time course of the response to SDGF is similar to that for NGF. Gap-43 mRNA induction by both SDGF and NGF is inhibited by dexamethasone, but dexamethasone has no effect on NGFI-A mRNA synthesis. These observations show that SDGF has a differentiation and survival promoting effect on PC12 cells in addition to its mitogenic activity on glial cells and fibroblasts.
 ...
PMID:Schwannoma-derived growth factor promotes the neuronal differentiation and survival of PC12 cells. 153 Sep 50

To determine the domains of the low-affinity nerve growth factor (NGF) receptor required for appropriate signal transduction, a series of hybrid receptors were constructed that consisted of the extracellular ligand-binding domain of the human epidermal growth factor (EGF) receptor (EGFR) fused to the transmembrane and cytoplasmic domains of the human low-affinity NGF receptor (NGFR). Transfection of these chimeric receptors into rat pheochromocytoma PC12 cells resulted in appropriate cell surface expression. Biological activity mediated by the EGF-NGF chimeric receptor was assayed by the induction of neurite outgrowth in response to EGF in stably transfected cells. Furthermore, the chimeric receptor mediated nuclear signaling, as evidenced by the specific induction of transin messenger RNA, an NGF-responsive gene. Neurite outgrowth was not observed with chimeric receptors that contained the transmembrane domain from the EGFR, suggesting that the membrane-spanning region and cytoplasmic domain of the low-affinity NGFR are necessary for signal transduction.
 ...
PMID:Chimeric NGF-EGF receptors define domains responsible for neuronal differentiation. 185 May 51

In previous work, we found that nerve growth factor (NGF) induced expression of the mRNA transcript encoding the metalloproteinase transin/stromelysin in PC12 cells. Transin was found, moreover, to be a "late" gene product whose expression correlated with neurites extension. In this study, various aspects of the NGF intracellular signaling pathway in PC12 cells are investigated. We show that the protein kinase inhibitor staurosporine, but not various other kinase inhibitors, specifically blocked the NGF induction of transin. Preliminary characterization of this staurosporine-sensitive kinase suggest that it does not correspond to a tyrosine kinase, nor various serine kinases, and that it is involved both at the transcriptional and posttranscriptional levels of transin gene regulation. In contrast to these effects of staurosporine, various activators of protein kinases C and A augmented the NGF induction of transin. Similar effects of these kinase inhibitors and activators were also observed with the expression of various immediate-early genes that have been proposed to mediate the transcriptional effects of NGF, including c-fos and c-jun. These data suggest, therefore, that the NGF induction of transin mRNA expression involves multiple protein kinases acting at a number of postreceptor regulatory steps in the NGF signaling pathway.
 ...
PMID:NGF-induction of the metalloproteinase-transin/stromelysin in PC12 cells: involvement of multiple protein kinases. 190 68

A dominant inhibitory mutation of Ha-ras which changes Ser-17 to Asn-17 in the gene product p21 [p21 (Asn-17)Ha-ras] has been used to investigate the role of ras in neuronal differentiation of PC12 cells. The growth of PC12 cells, in contrast to NIH 3T3 cells, was not inhibited by p21(Asn-17)Ha-ras expression. However, PC12 cells expressing the mutant Ha-ras protein showed a marked inhibition of morphological differentiation induced by nerve growth factor (NGF) or fibroblast growth factor (FGF). These cells, however, were still able to respond with neurite outgrowth to dibutyryl cyclic AMP and 12-O-tetradecanoylphorbol-13-acetate (TPA). Induction of early-response genes (fos, jun, and zif268) by NGF and FGF but not by TPA was also inhibited by high levels of p21(Asn-17)Ha-ras. However, lower levels of p21(Asn-17) expression were sufficient to block neuronal differentiation without inhibiting induction of these early-response genes. Induction of the secondary-response genes SCG10 and transin by NGF, like morphological differentiation, was inhibited by low levels of p21(Asn-17) whether or not induction of early-response genes was blocked. Therefore, although inhibition of ras function can inhibit early-response gene induction, this is not required to block morphological differentiation or secondary-response gene expression. These results suggest that ras proteins are involved in at least two different pathways of signal transduction from the NGF receptor, which can be distinguished by differential sensitivity to p21(Asn-17)Ha-ras. In addition, ras and protein kinase C can apparently induce early-response gene expression by independent pathways in PC12 cells.
 ...
PMID:Effect of a dominant inhibitory Ha-ras mutation on neuronal differentiation of PC12 cells. 211 94

Various proteases have been found to be released by the growth cones of developing neurons in culture and have been hypothesized to play a role in the process of axon elongation. We report here that nerve growth factor (NGF) induced the gene encoding the metalloprotease transin in PC12 cells with a time course coincident with the initial appearance of neurites by these cells. Acidic and basic fibroblast growth factors also stimulated transin mRNA expression and neurite outgrowth, whereas various other agents had no effects on either of these phenomena. In contrast, dexamethasone was found to inhibit the induction of transin mRNA when added with, or following, NGF treatment. Finally, we show that sequences contained within 750 bp of the 5' untranscribed region of the transin gene confer responsiveness to NGF and dexamethasone.
 ...
PMID:NGF induction of the gene encoding the protease transin accompanies neuronal differentiation in PC12 cells. 256 Jun 48

Matrix metalloproteinases have been implicated in various extracellular matrix remodeling events that occur during normal development and in a number of pathologies. In previous work with PC12 rat pheochromocytoma cells, we found that the matrix metalloproteinase stromelysin-1 (ST1) was highly induced by nerve growth factor (NGF), but not by epidermal growth factor (EGF). Here, we show that ST1 immunoreactivity is present in growth cones of NGF-treated PC12 cells, but not EGF-treated or untreated cells. To determine whether ST1 expression confers neurite invasiveness, three lines of PC12 cells were produced that constitutively express ST1 antisense mRNA. These lines expressed and secreted significantly reduced levels of ST1 protein, as determined by immunoblot and immunocytochemical methods, but otherwise responded normally to NGF-treatment by elaborating neurites. We found, however, that the neurites of these ST1 antisense cells showed a significantly reduced ability to penetrate a Matrigel reconstituted basal lamina, as compared to the parental cells, suggesting that ST1 confers neurite invasiveness. Finally, we show that ST1 is also expressed in vivo in sections through Embryonic Day 15 rat embryos, including neurons of both the peripheral and central nervous systems. These data indicate that ST1 may play a role in axonal growth in vivo, including a role in growth cone invasiveness.
 ...
PMID:The metalloproteinase stromelysin-1 (transin) mediates PC12 cell growth cone invasiveness through basal laminae. 759 58

Like neuronal cells, insulin producing cells (beta cells) possess nerve growth factor (NGF) binding sites and express mRNA coding for the low- and high-affinity NGF receptors, p75NGFR and Trk-A respectively. Although the role of NGF on neuronal cells is well documented, its function on beta cells is still unknown. As a first step towards the elucidation of the role of NGF on beta cells, we have characterized both types of NGF receptors on INS-1 cells, a beta cell line derived from a rat insulinoma and studied some early post-receptor events by comparing the signaling pathway of NGF in those cells and in PC12 cells, a well characterized NGF-responsive cell line. By polymerase chain reaction, immunocytochemistry, cross-linking and Western blot analysis, we clearly demonstrated that Trk-A and p75NGFR, the two NGF receptors expressed in INS-1 cells and PC12 cells are similar. Moreover, upon NGF treatment, Trk-A is phosphorylated on tyrosine residues in both cell types in the same dose- and time-dependent manner. These data clearly demonstrate that the first step of NGF signal transduction is similar in PC12 and INS-1 cells. Although early responsive genes like NGFI-A and c-fos are induced in both cell types upon NGF treatment, the induction of c-jun expression is restricted to PC12 cells. Furthermore, the expression of late responsive genes, such as vgf and transin, which are induced by NGF in PC12 cells, are not induced in INS-1 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Similarities and discrepancies in the signaling pathway for nerve growth factor in an insulin producing cell line and a neural crest-derived cell line. 773 95

The neuron-like differentiation of PC12 cells is induced by nerve growth factor (NGF) through stimulation of a membrane-bound protooncoprotein signaling pathway containing the NGF receptor Trk, the tyrosine kinase Src, and the GTP-binding protein Ras. The Raf-1 and B-raf protooncogenes encode cytoplasmic serine/threonine kinases that are stimulated by NGF in a Ras-dependent manner. To investigate the possible roles of cytoplasmic Raf kinases in eliciting neuronal differentiation, we have expressed the activated Raf-1 oncogene in PC12 cells. Expression of the raf oncogene results in the elaboration of a neuron-like phenotype, including neurite growth and the induction of the NGF-responsive genes NGFI-A and transin. The actions of activated Raf-1 and NGF are not additive. Furthermore, activated Raf-1 oncoprotein can prime cells for transcription-independent neurite growth by NGF and can elicit rapid neurite growth from NGF-primed cells. Our data indicate that the pathways utilized by NGF and activated raf to effect PC12 differentiation overlap and lead to the suggestion that cellular raf kinase activities play significant roles in transducing the differentiating signals of neuronal growth factors.
 ...
PMID:The cytoplasmic raf oncogene induces a neuronal phenotype in PC12 cells: a potential role for cellular raf kinases in neuronal growth factor signal transduction. 838 63


1 2 3 Next >>