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)

Serum amyloid A (SAA) is a major acute-phase plasma protein synthesized by the liver. In addition to the two major plasma isoforms described in humans (SAA1 and SAA2), a third form (SAA3) has been demonstrated in several other species and is distinguished by predominant extrahepatic expression. Two clones, Ch11g5-1-1 and HDg1-1, containing the human SAA3 gene are described in this report. The human SAA3 gene is comparable in organization to the SAA1 and SAA2 genes and shares with them 87% nucleotide identity in the region spanning exon 3 through exon 4. Sequences 5' to exon 3, however, are strikingly different from those in the SAA1 and SAA2 genes. For instance, the sequence deduced for amino acids 1-12 (exon 2) has only 25% identity with human SAA1 and SAA2; it most closely resembles that of rabbit SAA3 isolated from synovial fibroblast cultures (75% identity). Although rabbit SAA3 induces collagenase production in an autocrine fashion the human SAA3 gene is not expressed. This is shown by: (i) a single base insertion in the sequence corresponding to codon 31, (ii) the inability of a 918-bp fragment immediately upstream from SAA3 exon sequences to direct transcription of a chloramphenicol acetyltransferase reporter gene, and (iii) the absence of detectable human SAA3 in mRNA.
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PMID:Nonexpression of the human serum amyloid A three (SAA3) gene. 175 58

We report that nucleic acid sequence analysis of a full-length cDNA clone for a rabbit serum amyloid A (SAA)-like protein has identified this protein as more closely related to SAA3 than to SAA1. SAA3 induced collagenase synthesis in rabbit synovial fibroblasts, and immune IgG raised against this SAA protein abrogated the induction. Using antisera to immunoprecipitate biosynthetically labeled 3H-SAA and 3H-collagenase from culture medium, we compared the levels of SAA and collagenase synthesized by cultures of rabbit fibroblasts at early passage (passages 3-6) with those synthesized by late passage cells (passage 16). Comparatively high levels of both proteins were produced constitutively by fibroblasts at low passage. With increasing passage, levels of both proteins drop so that by passage 16, constitutive production of SAA and collagenase was only approximately 15-20% that of passage 3 cells. Cells at low passage could be readily stimulated with phorbol myristate acetate (PMA) or interleukin 1 (IL-1) to synthesize increased amounts of both SAA and collagenase. In passage 5 cells treated with PMA, we detected increased SAA mRNA by 1.5 h and collagenase mRNA by 5 h. However, older passage cells were more refractory to stimulation and required longer induction times. We suggest that SAA3 may be expressed by fibroblasts at sites of acute inflammation or injury, and that elevated levels of SAA3 may signify "activated" fibroblasts which are already producing increased amounts of collagenase constitutively and which are predisposed to further stimulation.
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PMID:Serum amyloid A (SAA3) produced by rabbit synovial fibroblasts treated with phorbol esters or interleukin 1 induces synthesis of collagenase and is neutralized with specific antiserum. 184 44

We have determined the genomic sequence of the human GSAA1 gene, a member of the family of acute-phase human serum amyloid A (SAA)-encoding genes. This sequence predicts a mature protein of 104 amino acids (aa), several of which differ from residues usually conserved in the sequence of SAA proteins isolated from serum. Despite coding differences, however, the four-exon structure of GSAA1 resembles that of other SAA genes in humans and mice. The N-terminal 25 aa of the mature GSAA1 protein are virtually identical to those of an 'SAA-like' autocrine collagenase inducer produced by rabbit synovial fibroblasts; the latter also differ from the corresponding aa found in SAA in serum. We propose that GSAA1 is the human gene coding for a protein closely related to the SAA, but which is adapted to this important autocrine cytokine function.
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PMID:The human serum amyloid A (SAA)-encoding gene GSAA1: nucleotide sequence and possible autocrine-collagenase-inducer function. 255 75

We found that the matrix metalloproteinases collagenase (MMP-1) and stromelysin (MMP-3) each has the ability to degrade a novel substrate, serum amyloid A (SAA3). SAA3 is a product of rabbit synovial fibroblasts stimulated with phorbol esters or interleukin-1, and it acts in an autocrine or paracrine manner to induce collagenase in both rabbit and human fibroblasts. Recombinant rabbit fibroblast procollagenase and human fibroblast prostromelysin were produced by baby hamster kidney (BHK) cells stably transfected with these genes, and latent enzyme was activated with aminophenylmercuric acetate (APMA). The Km for both enzymes was approximately 10 microM, and the Vmax for collagenase was approximately 6 pmol/minute/100 ng enzyme, while that for stromelysin was about 3-fold faster. Treatment of SAA3 with either enzyme generated a fragment of approx. 6 kDa that has the same amino terminus as the parent molecule, but this fragment was rapidly degraded. We have been unable to isolate C-terminal fragments, suggesting that the mature protein is cleaved at multiple sites and/or that the initial cleavage fragment is readily digested. The amino acid composition of the 6 kDa fragment suggests that the 14 kDa protein is cleaved at residues 50-57, a hydrophobic region that is conserved between rabbit SAA3 and human SAA1. We conclude that the ability of collagenase and stromelysin to degrade SAA3 broadens the repertoire of substrates for these matrix degrading enzymes, and we speculate that the presence of a feedback mechanism that can subvert the autocrine/paracrine stimulation of matrix-degrading enzymes may play a role in limiting matrix degradation during inflammatory conditions.
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PMID:The acute phase reactant serum amyloid A (SAA3) is a novel substrate for degradation by the metalloproteinases collagenase and stromelysin. 846 13