Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activity and/or expression of the mitogen-activated protein kinases c-Jun N-terminal kinase 1, p38 and extracellular signal-regulated kinases 1/2, as well as their substrates, the transcription factors c-Jun and activating transcription factor-2, were examined following systemic application of kainate in the cortex and hippocampus of the adult rat brain. The protein expression levels of all three mitogen-activated protein kinases remained constant during the observation period. Unexpectedly, c-Jun N-terminal kinase 1 was the only mitogen-activated protein kinase activated in this model of excitotoxicity, its activity raised from between 1 and 3 h moderate basal to maximal levels between 6 and 12 h. In contradistinction, activity of extracellular signal-regulated kinases 1/2 fell from their substantial basal levels and did not recover; activity of p38 was characterized by a high basal level that almost entirely disappeared and did not return to basal levels even 10 days after kainate application. c-Jun protein was rapidly expressed, with a maximum after 3 h and a slow decline after 12 h. Supershift assays revealed that, during the early induction phase of the c-jun gene, the proximal activator protein-1 (jun1) site of the c-jun promoter was mainly occupied by the constitutively expressed activating transcription factor-2, whereas the late induction correlated with the predominant binding of c-Jun and, to a lesser extent, activating transcription factor-2 to the distal activator protein-1 (jun2) site. The time-course of the N-terminal phosphorylation of c-Jun as determined by immunocytochemistry paralleled the activity of c-Jun N-terminal kinase 1 and showed a compartment-specific regulation between 3 and 12 h. A second set of supershift experiments demonstrated that c-Jun, but not activating transcription factor 2, bound to activator protein-1 sites in the promoter of substance P and collagenase genes, but not of the cyclo-oxygenase-2 gene. Our results demonstrate that activation of c-Jun N-terminal kinase 1, phosphorylation of c-Jun and selective occupation of the c-jun promoter by activating transcription factor-2 or c-Jun are part of the neuronal response following excitotoxicity that is considered as the mechanism for neuronal apoptosis in vivo. Some of these findings differ substantially from in vitro experiments and underline the necessity to analyse the neuronal stress pathways in the adult brain.
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PMID:Activity and expression of JNK1, p38 and ERK kinases, c-Jun N-terminal phosphorylation, and c-jun promoter binding in the adult rat brain following kainate-induced seizures. 1036 4

Oncostatin M (OSM), a member of the IL-6 superfamily of cytokines, is elevated in patients with rheumatoid arthritis and, in synergy with IL-1, promotes cartilage degeneration by matrix metalloproteinases (MMPs). We have previously shown that OSM induces MMP and tissue inhibitor of metalloproteinase-3 (TIMP-3) gene expression in chondrocytes by protein tyrosine kinase-dependent mechanisms. In the present study, we investigated signaling pathways regulating the induction of MMP and TIMP-3 genes by OSM. We demonstrate that OSM rapidly stimulated phosphorylation of Janus kinase (JAK) 1, JAK2, JAK3, and STAT1 as well as extracellular signal-regulated kinase (ERK) 1/2, p38, and c-Jun N-terminal kinase 1/2 mitogen-activated protein kinases in primary bovine and human chondrocytes. A JAK3-specific inhibitor blocked OSM-stimulated STAT1 tyrosine phosphorylation, DNA-binding activity of STAT1 as well as collagenase-1 (MMP-1), stromelysin-1 (MMP-3), collagenase-3 (MMP-13), and TIMP-3 RNA expression. In contrast, a JAK2-specific inhibitor, AG490, had no impact on these events. OSM-induced ERK1/2 activation was also not affected by these inhibitors. Similarly, curcumin (diferuloylmethane), an anti-inflammatory agent, suppressed OSM-stimulated STAT1 phosphorylation, DNA-binding activity of STAT1, and c-Jun N-terminal kinase activation without affecting JAK1, JAK2, JAK3, ERK1/2, and p38 phosphorylation. Curcumin also inhibited OSM-induced MMP-1, MMP-3, MMP-13, and TIMP-3 gene expression. Thus, OSM induces MMP and TIMP-3 genes in chondrocytes by activating JAK/STAT and mitogen-activated protein kinase signaling cascades, and interference with these pathways may be a useful approach to block the catabolic actions of OSM.
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PMID:Oncostatin M-induced matrix metalloproteinase and tissue inhibitor of metalloproteinase-3 genes expression in chondrocytes requires Janus kinase/STAT signaling pathway. 1120 8

Protein kinase C (PKC) has been shown to be a signal transducer during tumorigenesis, tumor cell invasion, and metastasis. Recent studies have reported that the PKC inhibitor, 7-hydroxystaurosporine, inhibits tumor cell invasion. However, the molecular mechanisms of this inhibition of invasion and metastasis are not well understood. In the present study, we attempt to clarify the mechanism by which H7, a PKC inhibitor, inhibits tumor cell invasion and metastasis in the melanoma cell line B16BL6. It was found that H7 inhibits B16BL6 cell invasion and metastasis. We also observed that H7 inhibits the mRNA expression and protein activities of matrix metalloproteinase (MMP)-1, -2, -9 and MT1-MMP. Furthermore, H7 suppresses phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2). However, other signal transduction factors, such as p38 mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase 1/2 (JNK1/2), were unaffected. Moreover, U0126, a MEK1/2 inhibitor, also inhibited B16BL6 cell invasion and metastasis, as well as the mRNA expression and protein activities of MMP-1, -2, -9 and MT1-MMP. This indicates that H7 inhibits signal transduction through the PKC/MEK/ERK pathway, thereby inhibiting B16BL6 cell invasion and metastasis. These results suggest that PKC inhibitors have potential clinical applications in the treatment of tumor cell metastasis.
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PMID:The protein kinase C inhibitor, H7, inhibits tumor cell invasion and metastasis in mouse melanoma via suppression of ERK1/2. 1763 10

Oxidative stress is related to the synthesis of matrix metalloproteinases (MMPs), which cause skin aging. The protective effects of mangiferin derived from Anemarrhena asphodeloides were investigated against hydrogen peroxide (H(2)O(2))-induced damage using human skin keratinocyte (HaCaT) cells. Mangiferin was found to scavenge intracellular reactive oxygen species (ROS), superoxide radicals, and hydroxyl radicals. ROS regulate MMPs gene expression and activation of proenzymes. Mangiferin inhibited H(2)O(2)-induced MMP-1 gene expression and protein levels as well as its activity. Moreover, it abrogated mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway and stress-activated protein kinase/extracellular signal-regulated kinase (SEK)-c-JUN N-terminal kinase (JNK) pathway, which are induced by H(2)O(2) treatment. And, it inhibited DNA binding activity of activator protein-1 (AP-1), a transcription factor of MMP-1 and downstream of ERK and JNK. Finally, it protected the human skin keratinocytes from H(2)O(2)-induced cell death. Taken together, these results indicate that mangiferin attenuated H(2)O(2)-induced MMP-1 activation via inhibition of ERK and JNK pathway and AP-1.
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PMID:Inhibition of matrix metalloproteinase-1 induced by oxidative stress in human keratinocytes by mangiferin isolated from Anemarrhena asphodeloides. 2214 20

p21-Activated serine-threonine kinase (PAK1) is implicated in breast cancer. We have shown previously that PAK1 is tyrosyl phosphorylated by prolactin (PRL)-activated Janus tyrosine kinase (JAK2). Although a role for both PRL and PAK1 in breast cancer is widely acknowledged, the mechanism remains poorly understood. In the present study, PRL-activated PAK1 stimulates the invasion of TMX2-28 human breast cancer cells through Matrigel. Three-dimensional (3D) collagen IV stimulates the secretion of the matrix proteases, metalloproteinase (MMP)-1 and -3 that is further enhanced by the PRL-dependent tyrosyl phosphorylation of PAK1. 3D collagen IV also stimulates the expression and secretion of MMP-2, but in contrast to MMP-1 and -3, PRL/PAK1 signaling down-regulates MMP-2 expression and secretion. In contrast, MMP-9 expression and secretion are stimulated by 3D collagen I, not collagen IV, and are not affected by PRL but are down-regulated by PAK1. MMP-1 and -3 are required and MMP-2 contributes to PRL-dependent invasion. ERK1/2 signaling appears to be required for the enhanced expression and secretion of MMP-1 and -3 and enhanced PRL-dependent invasion. p38 MAPK and c-Jun N-terminal kinase 1/2 pathways participate in production of MMP-1 and -3 as well as in PRL/PAK1-dependent cell invasion. Together, these data illustrate the complex interaction between the substratum and PRL/PAK1 signaling in human breast cancer cells and suggest a pivotal role for PRL-dependent PAK1 tyrosyl phosphorylation in MMP secretion.
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PMID:PAK1 regulates breast cancer cell invasion through secretion of matrix metalloproteinases in response to prolactin and three-dimensional collagen IV. 2374 93

Horse oil products have been used in skin care for a long time in traditional medicine, but the biological effects of horse oil on the skin remain unclear. This study was conducted to evaluate the protective effect of horse oil on ultraviolet B (UVB)-induced oxidative stress in human HaCaT keratinocytes. Horse oil significantly reduced UVB-induced intracellular reactive oxygen species and intracellular oxidative damage to lipids, proteins, and DNA. Horse oil absorbed light in the UVB range of the electromagnetic spectrum and suppressed the generation of cyclobutane pyrimidine dimers, a photoproduct of UVB irradiation. Western blotting showed that horse oil increased the UVB-induced Bcl-2/Bax ratio, inhibited mitochondria-mediated apoptosis and matrix metalloproteinase expression, and altered mitogen-activated protein kinase signaling-related proteins. These effects were conferred by increased phosphorylation of extracellular signal-regulated kinase 1/2 and decreased phosphorylation of p38 and c-Jun N-terminal kinase 1/2. Additionally, horse oil reduced UVB-induced binding of activator protein 1 to the matrix metalloproteinase-1 promoter site. These results indicate that horse oil protects human HaCaT keratinocytes from UVB-induced oxidative stress by absorbing UVB radiation and removing reactive oxygen species, thereby protecting cells from structural damage and preventing cell death and aging. In conclusion, horse oil is a potential skin protectant against skin damage involving oxidative stress.
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PMID:Horse Oil Mitigates Oxidative Damage to Human HaCaT Keratinocytes Caused by Ultraviolet B Irradiation. 3093 95