Cross-talk between different enhancer elements during mitogenic induction of the human stromelysin-1 gene.
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.
Kirstein
M
M
Fundación Valenciana de Investigaciones Biomédicas, Instituto de Investigaciones Citológicas, 46010 Valencia, Spain.
Sanz
L
L
Quiñones
S
S
Moscat
J
J
Diaz-Meco
M T
MT
Saus
J
J
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D004790:Enzyme Induction; D006801:Humans; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008934:Mitogens / Q000494:pharmacology*; D008969:Molecular Sequence Data; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011493:Protein Kinase C / Q000172:deficiency; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency; D011518:Proto-Oncogene Proteins / Q000172:deficiency; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
D004268:DNA-Binding Proteins; D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D011493:Protein Kinase C; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)