Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inflammatory cytokines like interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) are linked to abnormal cartilage and bone loss in a variety of pathological conditions. We have investigated the effect of TNF-alpha on the synthesis and/or steady-state mRNA levels of collagen, alkaline phosphatase (ALP), plasminogen activators (PAs) and their inhibitor PAI-1, and collagenases (MMPs) and their inhibitor TIMP-1 by human osteoblastic, HOS TE85, cells in monolayer cultures. HOS TE85 cells possess approximately 2000 TNF-alpha receptors per cell with a Kd value of 0.67 nM and receptor of approximately 60 kDa. TNF-alpha enhances urokinase-plasminogen activator (u-PA) activity and steady-state mRNA levels twofold without affecting tissue-plasminogen activator (t-PA) or PAI-1. The increase in u-PA mRNA is due to enhanced transcription of this gene. mRNA levels or activities of collagenase 1 (MMP-1), 72- and 92-kDa gelatinases (MMP-2 and MMP-9) are also nearly doubled with little change in the level of expression of TIMP-1. TNF-alpha does not significantly affect the activity or mRNA levels of ALP. TNF-alpha decreases collagen as well as general protein synthesis. However, the steady-state mRNA for the alpha 2 chain of collagen type I is increased three- to fourfold. These results show that TNF-alpha may increase pathological bone turnover by enhancing the rate of transcription of proteases capable of degrading the nonmineralized osteoid layer and decelerating the maturation of the extracellular matrix formed by osteoblasts.
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PMID:Modulation of proteases and their inhibitors in immortal human osteoblast-like cells by tumor necrosis factor-alpha in vitro. 808 23

We examined the anti-invasive activity of ursolic acid (UA) on the highly metastatic HT1080 human fibrosarcoma cell line. UA reduced tumor cell invasion through a reconstituted basement membrane in a transwell chamber. A significant down-regulation of matrix metalloproteinase-9 [MMP-9; Mr 92,000 gelatinase/type IV collagenase (gelatinase B)] by UA was detected by Northern blot analysis. However, MMP-2 [Mr 72,000 gelatinase/type IV collagenase (gelatinase A)] and membrane-type MMP were constantly expressed, and the expression of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 also was not changed after 3 and 6 days of treatment with UA. Quantitative gelatin-based zymography confirmed a markedly reduced expression of MMP-9 but not MMP-2 after treatment with UA. To confirm the UA-induced down-regulation of MMP-9 expression, we constructed a secreted alkaline phosphatase (SEAP) reporter vector including MMP-9 promoter. After transfection of MMP-9/SEAP reporter vector into HT1080 cells, reduced SEAP activity was detected after treatment with UA. These results suggest that down-regulation of MMP-9 contributes to the anti-invasive activity of UA in HT1080 cells.
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PMID:Anti-invasive activity of ursolic acid correlates with the reduced expression of matrix metalloproteinase-9 (MMP-9) in HT1080 human fibrosarcoma cells. 862 99

Osteoarthritis (OA) of the hip is invariably viewed as a disease primarily affecting the articular cartilage. Data presented in this report, however, demonstrate changes in the metabolic activity of the underlying trabecular bone tissue, the processes of which may represent a significant factor in the pathogenesis of hip OA. Trabecular bone tissue from OA subjects expressed significantly more matrix metalloproteinase (MMP)-2 (gelatinase A, 72 kDa type IV collagenase) when compared to age-matched osteoporotic (OP) and normal bone tissue. Alkaline phosphatase was also significantly elevated in OA bone tissue. The combination of increased MMP-2 and alkaline phosphatase indicates heightened collagen turnover in the subchondral bone compartment of osteoarthritic hips. The data obtained from this study warrant a closer investigation into the significance of these changes in OA and emphasize the multifactorial elements of the whole joint in the whole joint in the overall disease process.
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PMID:Biochemical evidence for altered subchondral bone collagen metabolism in osteoarthritis of the hip. 911 67

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is synthesized as a membrane-anchored precursor that is cleaved to release the soluble mature growth factor. The two forms are active as juxtacrine and paracrine/autocrine growth factors, respectively. The enzymes that process the HB-EGF transmembrane form are unknown. Accordingly, an in vitro assay was established using a fusion protein in which alkaline phosphatase (AP) replaced the transmembrane and cytoplasmic domains of HB-EGF (HB-EGF JM-AP). The fusion protein was anchored to agarose beads coated with anti-AP antibodies. Several matrix metalloproteinases (MMPs) were tested for the ability to release soluble HB-EGF in the in vitro system. MMP-3 released soluble 12-kDa immunoreactive and mitogenic HB-EGF within 30 min. On the other hand neither MMP-2 nor MMP-9 had any cleavage activities. A non-cleavable mutant was prepared by replacing the juxtamembrane (JM) region of HB-EGF with the JM region of CD4. The mutant HB-EGF, which in its full-length form was as active a juxtacrine growth factor as was the wild type HB-EGF in vivo, was not cleaved by MMP-3 in the in vitro assay. The C-terminal portion of the cleaved HB-EGF JM-AP that remained attached to the anti-AP beads was N-terminally sequenced and the MMP-3 cleavage site was determined to be Glu151-Asn152, a site within the JM domain. MMP-3 treatment also released soluble HB-EGF in vivo from MC2 cells expressing transmembrane HB-EGF precursor, at a level of about 2-fold above control. It was concluded that MMP-3 cleaves HB-EGF at a specific site in the JM domain and that this enzyme might regulate the conversion of HB-EGF from being a juxtacrine to a paracrine/autocrine growth factor.
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PMID:Matrix metalloproteinase-3 releases active heparin-binding EGF-like growth factor by cleavage at a specific juxtamembrane site. 939 17

Structural changes in the extracellular matrix (ECM) are necessary for cell migration during tissue remodeling and local neoplastic cell invasion. The matrix metalloproteinases (MMPs) and their inhibitors have been shown to be critical modulators of ECM composition and are thus, crucial in tumor cell invasion and metastasis. The immunocytochemical profile of MMP-2, -3, -9, -10, and -13 expression was observed in 24 primary human childhood astrocytomas (ASTRs) employing an indirect alkaline phosphatase conjugated antigen detection technique. Evaluation of the results was based on (a) the percent of neoplastically transformed cells that reacted positively and (b) a measure of staining intensity [graded from A (highest) to D (negative)]. The two forms of stromelysin, MMP-3 and -10, share 82% sequence homology, but exhibit differences in cellular synthesis and inducibility by cytokines and growth factors in vitro. Strong overall expression of MMP-3 and -10 was found in ASTRs, especially in the ECM adjacent to blood vessels. Positive immunoreactivity could be seen for these two MMPs in the ECM surrounding over 90% of the neoplastically transformed cells (+4) and the staining intensity was also the strongest possible (A,B). No immunoreactivity was detected using antibodies directed against MMP-2, -9, and -13. Based on these results, MMP-3 and -10 are implicated in the pathogenesis of pediatric ASTRs. Further characterization of the expression and utilization of MMPs and their inhibitors in the progression of ASTRs may establish differential regulation and utilization of the various MMPs during the progression of glial tumors, from low-grade pilocytic ASTR to high-grade glioblastoma multiforme.
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PMID:Matrix metalloproteinase expression in childhood astrocytomas. 1106 55

Structural changes in the extracellular matrix (ECM) are necessary for cell migration during tissue remodeling and tumor invasion. The matrix metalloproteinases (MMPs) and their inhibitors have been shown to be critical modulators of ECM composition and are thus crucial in neoplastic cell invasion and metastasis. Expression of MMP-2, -3, -9, -10, and -13 was investigated in human hepatocellular carcinomas (HCCs) employing an indirect alkaline phosphatase conjugated immunocytochemical technique. Evaluation of the results was based on (a) the persent of neoplastically transformed cells/surrounding stroma that reacted positively and (b) a measure of staining intensity [graded from A (highest) to D]. The two forms of stromelysin, MMP-3 and -10, share 82% sequence homology, but exhibit differences in cellular synthesis and inducibility by cytokines and growth factors in vitro. Strong overall expression of MMP-3 and -10 was found in HCCs, especially in the ECM adjacent to blood vessels. Positive immunoreactivity could be seen for these two MMPs in the ECM surrounding over 90% of the neoplastically transformed cells (++++), and the staining intensity was also the strongest possible (A,B). No immunoreactivity was detected using antibodies directed against MMP-2, -9, and -13.
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PMID:Immunocytochemical detection of MMP-3 and -10 expression in hepatocellular carcinomas. 1121 Aug 57

Matrix metalloproteinases (MMP) are a family of zinc-dependent enzymes which degrade various components of the extracellular matrix (ECM) and play an important role in facilitating neoplastic cell invasion and metastasis. Structural changes in the extracellular matrix are necessary for cell migration during tissue remodeling and tumor invasion. Expression of MMP-2, -3, -9, -10, and -13 was investigated in both spontaneous and xenografted (cells derived from an established cell-line [DAOY#3]) childhood medulloblastomas (MEDs)/primitive neuroectodermal tumors (PNETs) employing an indirect alkaline phosphatase conjugated immunocytochemical technique. Evaluation of the results was based on (a) the percent of neoplastically transformed tissue that reacted positively and (b) a measure of staining intensity [graded from A (highest) to D]. The two forms of stromelysin (SL), types 1 (MMP-3) and 2 (MMP-10), share 82% sequence homology, but exhibit differences in cellular synthesis and inducibility by cytokines and growth factors in vitro. Strong overall expression of MMP-3 and -10 was found only in the spontaneous MEDs/PNETs, especially in the ECM adjacent to blood vessels. Positive immunoreactivity could be seen for these two MMPs in the ECM surrounding over 90% of the neoplastically transformed cells in the spontaneous cases, and the staining intensity was also the strongest possible (A,B). Focal (surrounding less than 10% of the neoplastically transformed cells) but strong (A,B) immunoreactivity for collagenase-3 (MMP-13) was also only detected in spontaneous MEDs/PNETs, an endopeptidase characterized by a potent degrading activity against a wide spectrum of substrates. Weak (surrounding anywhere between 10% and 90% of the neoplastically transformed cells, and of B and B,C intensity) expression of MMP-2 (gelatinase A) and MMP-9 (gelatinase B), two cytokine-induced MMPs, was also observed in the spontaneous cases. Staining for MMP-2 was negative in the xenografted MEDs/PNETs. The only positive immunoreactivity in the xenografted MEDs/PNETs was observed in the case of MMP-9, with expression of strong intensity in the ECM surrounding over 90% of the neoplastically transformed xenografted MED/PNET cells (++++; A,B). It is clear that the activation of MMPs and their inhibitors occurs in a very well orchestrated manner. The data presented here suggest that there are significant differences in the pathophysiology of spontaneous and xenografted human neoplasms, which further establishes the already detected limitations of such models in preclinical cancer research.
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PMID:Significant differences in the matrix metalloproteinase expression profiles of spontaneous medulloblastomas/primitive neuroectodermal tumors as compared with their xenografted, established tumor cell line derived counterparts. 1121 45

The matrix metalloproteinases (MMPs) are a family of enzymes that degrade the extracellular matrix (ECM) and are considered to be important in neoplastic cell invasion and metastasis. Structural changes in the extracellular matrix are necessary for cell migration during tissue remodeling and neoplastic invasion. Expression of MMP-2, -3, -9, -10, and -13 was investigated in human childhood medulloblastomas (MEDs)/primitive neuroectodermal tumors (PNETs) employing an indirect alkaline phosphatase conjugated immunohistochemical antigen detection technique. Evaluation of the results was based on (a) the percent of neoplastically transformed tissue that reacted positively and (b) a measure of immunoreactivity or staining intensity [graded from A (highest) to D (negative)]. Strong overall expression of MMP-3 and -10 was found in MEDs/PNETs, especially in the ECM adjacent to blood vessels. Positive immunoreactivity was identified for these two MMPs in the ECM surrounding over 90% of the neoplastically transformed cells with the staining intensity being also the strongest possible (A,B). These two forms of stromelysin (SL), types 1 (MMP-3) and 2 (MMP-10), share 82% sequence homology, but exhibit differences in cellular synthesis and inducibility by cytokines and growth factors in vitro. Focal (surrounding less than 10% of the neoplastically transformed cells) but strong (A,B) immunoreactivity was determined for collagenase-3 (MMP-13), an endopeptidase characterized by a potent degrading activity against a wide spectrum of substrates. Weak (surrounding anywhere between 10% and 90% of the neoplastically transformed cells, and of B and B,C intensity) expression of MMP-2 (gelatinase A) and MMP-9 (gelatinase B), two cytokine-induced MMPs, was also observed. It is clear that the activation of MMPs and their inhibitors occurs in a very well orchestrated manner. The necessity of these same enzymes for the extravasation and infiltration of lymphocytes into regions of chronic local inflammation, as associated with neoplastically transformed masses of cells, may aid the transformed cells which have already acquired a more aggressive, metastatic immunophenotype (IP) to enter the peripheral circulation. Further characterization of the expression and utilization of MMPs and their inhibitors in the progression of solid human malignancies should lead to the development of novel anti-cancer therapies.
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PMID:Matrix metalloproteinase expression in childhood medulloblastomas/primitive neuroectodermal tumors. 1121 44

The matrix metalloproteinases (MMPs) are a family of enzymes that degrade the extracellular matrix (ECM) and are considered to be important in neoplastic cell invasion and metastasis. Structural changes in the extracellular matrix are necessary for cell migration during tissue remodeling and neoplastic cell invasion. Histochemical expression of MMP-2, -3, -9, -10, and -13 was observed in 19 human colorectal carcinomas (CCs) employing an indirect alkaline phosphatase (AP) conjugated antigen detection technique. Evaluation of the results was based on (a) the percent of neoplastically transformed cells that reacted positively and (b) a measure of staining intensity [graded from A (highest) to D]. The two forms of stromelysin (SL), types 1 (MMP-3) and 2 (MMP-10), share 82% sequence homology, but exhibit differences in cellular synthesis and inducibility by cytokines and growth factors in vitro. Strong overall expression of MMP-3 and -10 was found in all CC cases observed, especially in the ECM adjacent to blood vessels. Positive immunoreactivity could be seen for these two MMPs in the ECM surrounding over 90% of the neoplastically transformed cells, and the staining intensity was also the strongest possible (A,B). Weak (surrounding anywhere between 10% and 90% of the neoplastically transformed cells, and of strong A,B intensity) expression of MMP-2 (gelatinase A) and MMP-9 (gelatinase B), two cytokine-induced MMPs, was also observed in CCs. Expression of collagenase-3 (MMP-13), an endopeptidase characterized by a potent degrading activity against a wide spectrum of substrates, was not defined in the CCs cases observed by us. It is clear that the activation of MMPs and their inhibitors occurs in a very well orchestrated manner. The necessity of these same enzymes for the extravasation and infiltration of lymphocytes into regions of chronic local inflammation, as associated with neoplastically transformed masses of cells, may aid the transformed cells which have already acquired a metastatic immunophenotype to enter the peripheral circulation. Further characterization of the expression and utilization of MMPs and their inhibitors in the progression of solid human neoplasms should lead to the development of novel anti-cancer therapies.
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PMID:Prognostic significance of matrix metalloproteinase expression in colorectal carcinomas. 1121 43

Structural changes in the extracellular matrix (ECM) are necessary for cell migration during tissue remodeling and tumor invasion. The matrix metalloproteinases (MMPs) and their inhibitors have been shown to be critical modulators of ECM composition and are, thus, crucial in neoplastic cell invasion and metastasis. Expression of MMP-2, -3, -9, -10, and -13 was investigated in human malignant melanomas (MMs) employing an indirect alkaline phosphatase conjugated immunocytochemical technique. Evaluation of the results was based on (a) the percent of neoplastically transformed cells/surrounding stroma that reacted positively and (b) a measure of staining intensity [graded from A (highest) to D]. The two forms of stromelysin, MMP-3 and -10, share 82% sequence homology, but exhibit differences in cellular synthesis and inducibility by cytokines and growth factors in vitro. Strong overall expression of MMP-3 and -10 was found in MMs, especially in the ECM adjacent to blood vessels. Positive immunoreactivity could be seen for these two MMPs in the ECM surrounding over 90% of the neoplastically transformed cells (++++), and the staining intensity was also the strongest possible (A,B). Focal (+), high intensity (A,B) staining could be detected for MMP-2, -9, and -13. Thus, it seems that the stromelysins are involved in the generalized growth and expansion of the neoplastic cell mass, while MMP-2, -9 and -13 are involved in the neoangiogenic and focal clonal selection and expansion phenomena associated with in situ tumor progression, invasion of the microvasculature, and metastasis.
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PMID:Matrix metalloproteinase expression in malignant melanomas: tumor-extracellular matrix interactions in invasion and metastasis. 1128 31


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