Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.28 (chloramphenicol acetyltransferase)
 5,100 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Collagenase, the only enzyme active at neutral pH that initiates collagen degradation, is a major gene product of fibroblasts that have been stimulated with a variety of agents, including phorbol esters. To study mechanisms controlling collagenase gene expression, we transiently transfected rabbit synovial fibroblasts with chimeric constructs containing up to 1.2 kb of the rabbit collagenase 5'-flanking DNA linked to the chloramphenicol acetyltransferase gene (CAT). Our data indicate that the magnitude of the phorbol response is directly linked to the size of the promoter fragment and that the smallest piece of promoter DNA conferring phorbol inducibility is 127 bp. Deletional and mutational analysis of this fragment revealed that the AP-1 sequence alone is insufficient for phorbol inducibility and the presence of at least two additional sequences (a PEA3-like element and a sequence that includes 5'-TTCA-3') is required. In addition, a substantial increase in responsiveness is seen when a fragment containing 182 bp of 5'-flanking DNA is transfected, implicating a 36 bp region located between -182 and -149 as an enhancer. We conclude (1) that the AP-1 sequence is necessary but insufficient for expression of collagenase in adult fibroblasts, (2) that phorbol inducibility depends on cooperation among several sequence elements within the collagenase promoter, and (3) that regulation of this promoter is more complex than previously described.
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PMID:The AP-1 sequence is necessary but not sufficient for phorbol induction of collagenase in fibroblasts. 185 Jun 29

Collagenase production by synovial fibroblast-like cells (synoviocytes) plays a major role in cartilage and bone destruction in rheumatoid arthritis. Interleukin-1 (IL-1) increases collagenase secretion by elevating the steady state levels of collagenase mRNA in cultured rheumatoid synoviocytes, while all-trans-retinoic acid (RA) has the opposite effect. We have studied the regulation of collagenase gene transcription by IL-1 and RA in synoviocytes by transient transfection of plasmid constructs containing deletion mutants of the 5'-flanking region of the collagenase gene or the isolated phorbol ester-responsive element ligated to a chloramphenicol acetyltransferase reporter gene. We show that the phorbol ester-responsive element of the collagenase gene mediates both positive and negative regulatory effects, respectively, of IL-1 and RA on transcription. In addition, we show that IL-1 and 12-O-tetradecanoyl-phorbol-13-acetate transiently induce c-jun and c-fos expression and that retinoic acid inhibits IL-1 and 12-O-tetradecanoyl-phorbol-13-acetate induction of c-fos, but not c-jun. These results suggest that RA inhibits collagenase transcription at least in part through inhibition of c-fos.
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PMID:Interleukin-1 stimulates and all-trans-retinoic acid inhibits collagenase gene expression through its 5' activator protein-1-binding site. 217 24