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) activating factor-1 (SAF-1) is an inducible transcription factor that plays a key role in the regulation of several inflammation-responsive genes including SAA and matrix metalloproteinase-1. Increased synthesis of SAA and matrix metalloproteinase-1 is associated with pathogenesis of several diseases including amyloidosis, arthritis, and atherosclerosis. Previously, we showed in vivo interaction of SAF-1 and protein kinase A (PKA) and presented evidence for induction of SAF-1-regulated genes by a PKA signaling pathway. Here we demonstrate a mechanism by which PKA increases functional activities of SAF-1. Site-directed mutagenesis and phosphorylation analyses revealed two sites in the SAF-1 protein, serine 187 and threonine 386, as the target of PKA. Interestingly, mutation of both PKA phosphorylation sites created a highly active SAF-1 protein with high DNA-binding ability. Furthermore, we found that terminal deletion of SAF-1 protein from either end creates SAF-1 isoforms that are highly transcriptionally active. Partial proteolysis experiments indicated that unphosphorylated and phosphorylated SAF-1 proteins are structurally distinct. Together these results suggest that under native condition, N and C termini of SAF-1 are engaged in an inhibitory intramolecular interaction. PKA-mediated phosphorylation increases transcriptional activity of SAF-1 by unmasking the DNA-binding domain.
 ...
PMID:Protein kinase A signaling pathway regulates transcriptional activity of SAF-1 by unmasking its DNA-binding domains. 1269 57

A number of risk factors including biomechanical stress on the articular cartilage imposed by joint overloading due to obesity, repetitive damage of the joint tissues by injury of the menisci and ligaments, and abnormal joint alignment play a significant role in the onset of osteoarthritis (OA). Genetic predisposition can also lead to the formation of defective cartilage matrix because of abnormal gene expression in the cartilage-specific cells. Another important biochemical event in OA is the consequence of inflammation. It has been shown that synovial inflammation triggers the synthesis of biological stimuli such as cytokines and growth factors which subsequently reach the chondrocyte cells of the articular cartilage activating inflammatory events in the chondrocytes leading to cartilage destruction. In addition to cartilage degradation, hypertrophy of the subchondral bone and osteophyte formation at the joint margins also takes place in OA. Both processes involve abnormal expression of a number of genes including matrix metalloproteinases (MMPs) for cartilage degradation and those associated with bone formation during osteophyte development. To address how diverse groups of genes are activated in OA chondrocyte, we have studied their induction mechanism. We present evidence for abundant expression of an inflammation-responsive transcription factor, SAF-1, in moderate to severely damaged OA cartilage tissues. In contrast, cells in normal cartilage matrix contain very low level of SAF-1 protein. SAF-1 is identified as a major regulator of increased synthesis of MMP-1 and -9 and pro-angiogenic factor, vascular endothelial growth factor (VEGF). While VEGF by stimulating angiogenesis plays a key role in new bone formation in osteophyte, increase of MMP-1 and -9 is instrumental for cartilage erosion in the pathogenesis of OA. Increased expression in degenerated cartilage matrix and in the osteophytes indicate for a key regulatory role of SAF-1 in directing catabolic matrix degrading and anabolic matrix regenerating activities.
 ...
PMID:An inflammation-responsive transcription factor in the pathophysiology of osteoarthritis. 1883 40

Previously we determined that inflammation responsive transcription factors AP-1 and SAF-1 synergistically regulate transcriptional induction of the MMP-1 gene. The present study investigated the underlying molecular mechanism of cooperativity between these two different groups of transcription factors. We present evidence that knockdown of SAF-1 by small interfering RNAs inhibits AP-1-mediated increase of human MMP-1 expression. The two key members of the AP-1 family of proteins, c-Fos and c-Jun, and SAF-1 form a ternary protein complex, which has markedly higher DNA binding activity than either a SAF-1 homodimer or a c-Fos/c-Jun heterodimer. The increased DNA binding activity of the ternary complex is translated into a striking enhancement of their transcriptional activity by which synergistic transcriptional induction of MMP-1 expression is achieved. The SAF-1.c-Fos.c-Jun ternary complex efficiently promotes transcription from both SAF-1 and AP-1 sites of human MMP-1 promoter. The physical interaction between SAF-1 and AP-1 was demonstrated both in vitro by Far-Western and antibody pulldown assays with recombinant proteins and in vivo by chromatin immunoprecipitation (ChIP), re-ChIP, and co-immunoprecipitation analyses. Two distinct but adjacent domains in SAF-1 are involved in protein-protein contact with c-Fos and c-Jun; one domain resides within two N-terminal polyalanine tracts, and the other is present within the first two zinc finger motifs. Together these findings delineate the mechanism of synergy and the essential role of SAF-1 and AP-1 in up-regulating human MMP-1 expression under various inflammatory conditions.
 ...
PMID:Transcriptional synergy mediated by SAF-1 and AP-1: critical role of N-terminal polyalanine and two zinc finger domains of SAF-1. 1902 85