| First Author | Kumar D | Year | 2009 |
| Journal | J Biol Chem | Volume | 284 |
| Issue | 3 | Pages | 1853-62 |
| PubMed ID | 19028685 | Mgi Jnum | J:217993 |
| Mgi Id | MGI:5616316 | Doi | 10.1074/jbc.M806289200 |
| Citation | Kumar D, et al. (2009) Transcriptional synergy mediated by SAF-1 and AP-1: critical role of N-terminal polyalanine and two zinc finger domains of SAF-1. J Biol Chem 284(3):1853-62 |
| abstractText | 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. |
