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)

An IL-10 responsive signal protein, termed IL-10E1, was cloned from human prostate cancer PC-3 ML cells based on its binding affinity for a novel enhancer element (i.e., HTE-1: 5'-CACGATGACTCATCACTGTTGAAAGACA-3') of the Tissue Inhibitor of metalloproteinase-1 (TIMP-1) gene. Electrophoretic mobility shift assays (EMSAs) and enzyme linked immuno-sandwich assays (ELISAs) showed that IL-10 stimulated the rapid translocation of IL-10E1 to the nucleus and the activation of TIMP-1 expression in 4 different androgen dependent primary prostate tumor lines generated in our laboratory (i.e. HPCA-5a, 5b, 5c and 5d lines). IL-10 signaling was blocked by a variety of agents, including IL-10 receptor antibodies, alpha-toxin, and Genistein. The inhibition of IL-10 signaling and IL-10E1 expression correlated directly with a significant decrease in TIMP-1 expression by the HPCA-5a, 5b, 5c and 5d cell lines. Following permanent transfection of HPCA-5a and 5c cells with the IL-10 gene the growth of tumor xenografts in SCID CB17 mice was severely retarded, yielding tiny, poorly vascularized tumors by approximately 90 days post-inoculation s.c. ELISAs showed that these tumors expressed elevated levels of IL-10, IL-10E1 and TIMP-1 compared with tumors from non-transfected or Mock transfected cell lines. We conclude that the IL-10/IL-10 receptor axis (and IL-10E1 signaling) regulation of TIMP-1 expression plays a key role in inhibiting tumor growth, perhaps by blocking tumor vascularization.
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PMID:IL-10/IL-10 receptor signaling regulates TIMP-1 expression in primary human prostate tumor lines. 1249 89

Interleukin 10 (IL-10) stimulates rapid nuclear translocation and binding of a 22 kDa protein, termed interleukin 10 enhancer 1 (IL-10E1), to a novel enhancer element (i.e. HTE-1) of the tissue inhibitor of metalloproteinase-1 (TIMP-1) gene to upregulate TIMP-1 expression. IL-10E1 signaling involves tyrosine phosphorylation of the IL-10R JAK1 (Janus kinase) and TYK2 (tyrosine kinase) receptor kinases and tyrosine phosphorylation of two tyrosine moieties (Y57 and Y62) of a LIM domain of the IL-10E1 protein. In this paper, the studies showed that two tyrosine residues (Tyr(446) and Tyr(496)) located in the cytoplasmic domain of the IL-10R alpha chain were required for receptor function, and for phosphorylation and activation of IL-10E1. Immunoprecipitation studies revealed that 12 amino-acid peptides encompassing either of these two tyrosine residues in phosphorylated form coprecipitated IL-10E1 and blocked ligand-dependent IL-10E1 phosphorylation in a cell-free system. In contrast, peptides containing serine substitutions for Tyr(446) and Tyr(496), and tyrosine-phosphorylated peptides containing Tyr(230) or Tyr(252/259) did not prevent IL-10E1 activation or signaling. To confirm these observations in vivo, fusion protein constructs were made between a modified form of green fluorescent protein or GFP and the intact IL-10E1 protein (IL-10E1-MmGFP) and n-terminal peptides of the IL-10E1 protein (i.e. nt-nls-MmGFP and mutant sequences identified as nt-nls mC61-MmGFP and nt-nls mY57/mY62-MmGFP peptides). Confocal microscopy revealed that IL-10 triggered transport to the nucleus of IL-10E1-MmGFP, nt-nls-MmGFP, and nt-nls mC61-MmGFP by 10-30 min in HPCA-10a (human prostrate cancer cells; derived from Gleason sum 10 tumor tissue) cells. IL-10 failed to induce nuclear translocation of the mY57/mY62-MmGFP peptides with point mutations of the two tyrosine groups. Coinjection of nt-nls-MmGFP with the IL-10R Tyr(446) and Tyr(496) amino-acid residues completely blocked ligand signaling. Coinjection of peptides containing either serine substitutions for Tyr(446) and Tyr(496) or Tyr(230) and Tyr(252/259) failed to block nt-nls-MmGFP signaling. The data demonstrate that IL-10E1 is directly recruited to the ligand-activated IL-10R by binding to specific phosphotyrosine groups which control tyrosine phosphorylation of the LIM domain of the IL-10E1 protein (i.e. Y57/Y62 groups) and IL-10E1 activation.
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PMID:IL-10 signaling via IL-10E1 is dependent on tyrosine phosphorylation in the IL-10R alpha chain in human primary prostate cancer cell lines. 1280 85

The interleukin-10 (IL-10) activation of Janus kinase (JAK) family members (JAK1/TYK2) and IL-10E1 is subsequently inactivated by approximately 3-4 h in primary prostate tumor lines. We examined the effect of proteasome inhibition on IL-10 activation of the IL-10E1 pathway following stimulation of HPCA-10a cells. Treatment of HPCA-10a cells with the proteasome inhibitor, N-acetyl-L-leucinyl-L-leucinyl-norleucinal (LLnL), led to stable tyrosine phosphorylation of the IL-10 receptor and IL-10E1 following stimulation. Further investigation showed that these stable phosphorylation events were the result of prolonged activation of JAK1 and TYK2 plus IL-10E1. IL-10E1 signaling normally induced the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and LLnL treatment of the HPCA-10a and HPCA-10c cells significantly enhanced IL-10 induction of TIMP-1 levels to block tumor cell invasion in modified Boyden chamber invasion assays. These observations were confirmed using pharmacologic inhibitors by Western blot and ELISAs. In the presence of LLnL, stable phosphorylation of IL-10E1 and induction of TIMP-1 was abrogated if the tyrosine kinase inhibitor, staurosporine, was added. The effect of staurosporine on IL-10E1 phosphorylation and TIMP-1 could be overcome if the phosphatase inhibitor, vanadate, was also added, suggesting that phosphorylated IL-10E1 could be stabilized by phosphatase, but not by proteasome inhibition. These observations are consistent with the hypothesis that proteasome-mediated protein degradation can modulate the activity of the IL-10E1 pathway and TIMP-1 induction by regulating the deactivation of JAK1/TYK2.
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PMID:Interleukin-10 activation of the interleukin-10E1 pathway and tissue inhibitor of metalloproteinase-1 expression is enhanced by proteasome inhibitors in primary prostate tumor lines. 1286 Oct 49