Cross-talk between different enhancer elements during mitogenic induction of the human stromelysin-1 gene.

TitleCross-talk between different enhancer elements during mitogenic induction of the human stromelysin-1 gene.
Publication TypeJournal Article
Year of Publication1996
AuthorsKirstein M, Sanz L, QuiƱones S, Moscat J, Diaz-Meco MT, Saus J
JournalJ Biol Chem
Date Published1996 Jul 26
Keywords3T3 Cells, Animals, Base Sequence, DNA-Binding Proteins, Enhancer Elements, Genetic, Enzyme Induction, Humans, Matrix Metalloproteinase 3, Metalloendopeptidases, Mice, Mitogens, Molecular Sequence Data, Platelet-Derived Growth Factor, Protein Kinase C, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-jun, Proto-Oncogene Proteins c-raf, Proto-Oncogene Proteins p21(ras), Recombinant Proteins, Transcription Factor AP-1, Transcription, Genetic, Transfection

Platelet-derived growth factor (PDGF) induces the expression of human stromelysin-1, a matrix metalloproteinase involved in tumor invasion and metastasis. Here it is shown that stromelysin-1 gene induction by PDGF depends on Ras and involves three previously identified promoter elements (the stromelysin-1 PDGF-responsive element (SPRE) site, the two head-to-head polyomavirus enhancer A-binding protein-3 (PEA3) sites, and the activator protein-1 (AP-1) binding site). During mitogenic induction, these responsive elements appear to be organized in two independent transcriptional units, SPRE-AP-1 and PEA3-AP-1, which result from specific element cross-talking. Interestingly, expression of a dominant negative mutant of Raf-1 significantly interfered with the induction through PEA3-AP-1 but not with that operating through SPRE-AP-1. Conversely, only the induction operating through SPRE-AP-1 was affected significantly by the expression of a dominant negative mutant of the atypical lambda/iota protein kinase C (lambda/iotaPKC). These data strongly suggest that the signal triggered by PDGF flows through Ras and bifurcates toward two distinct pathways, one operating through Raf and involving PEA3-AP-1 and the other one Raf-independent, operating through lambda/iotaPKC and SPRE-AP-1. Furthermore, we present evidence suggesting that the novel SPRE-binding transcription factor SPBP cross-couples with c-Jun to transactivate the SPRE site.

Alternate JournalJ Biol Chem
PubMed ID8663478
Related Faculty: 
Jorge Moscat, Ph.D. Maria Diaz-Meco Conde, Ph.D.

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