Abstract |
Gelatinase A, also denoted matrix metalloproteinase 2, plays multiple critical roles in the neoplastic process, including facilitation of neoangiogenesis and formation of distal metastases. The transcriptional regulation of the gelatinase A gene is under the control of strong, evolutionarily conserved cis-acting enhancer elements, designated the r2 (human) or RE-1 (rat), that harbor contiguous binding motifs for the transcription factors activating protein-2 (AP2), p53, and YB-1. Using recombinant transcription factors, complex patterns of RE-1 binding were observed by electrophoretic mobility shift assay. Increased complex formation was detected with the AP2/YB-1 and AP2/p53 combinations, while YB-1 competed with p53 for binding. The combination of AP2, p53, and YB-1 yielded novel ternary complexes, particularly when binding to single-stranded RE-1 probes. Transient transfection of hepatocellular carcinoma cell lines with a series of gelatinase A luciferase reporter constructs were in accordance with the binding patterns determined by electrophoretic mobility shift assay. Combined AP2 and p53 increased gelatinase A luciferase reporter activity significantly, and the inclusion of YB-1 yielded further increase in both reporter activity and secreted levels of gelatinase A protein. YB-1 and p53 expression are increased following multiple genotoxic stresses, including irradiation, and the synergistic interactions of these induced transcription factors with the widely expressed AP2 protein provide a probable pathophysiologic mechanism for the enhanced tumor cell synthesis of gelatinase A induced by radiation.
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Authors | Peter R Mertens, Karin Steinmann, Maria A Alfonso-Jaume, Abdelaziz En-Nia, Yi Sun, David H Lovett |
Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 277
Issue 28
Pg. 24875-82
(Jul 12 2002)
ISSN: 0021-9258 [Print] United States |
PMID | 11973333
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- CCAAT-Enhancer-Binding Proteins
- DNA, Single-Stranded
- DNA-Binding Proteins
- NFI Transcription Factors
- Nuclear Proteins
- Transcription Factor AP-2
- Transcription Factors
- Tumor Suppressor Protein p53
- Y-Box-Binding Protein 1
- YBX1 protein, human
- Matrix Metalloproteinase 2
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Topics |
- Animals
- Base Sequence
- CCAAT-Enhancer-Binding Proteins
(metabolism)
- DNA, Single-Stranded
(metabolism)
- DNA-Binding Proteins
(metabolism)
- Enhancer Elements, Genetic
- Matrix Metalloproteinase 2
(biosynthesis, genetics, metabolism)
- Molecular Sequence Data
- NFI Transcription Factors
- Nuclear Proteins
- Promoter Regions, Genetic
- Protein Binding
- Rats
- Sequence Homology, Nucleic Acid
- Templates, Genetic
- Transcription Factor AP-2
- Transcription Factors
(metabolism)
- Transcriptional Activation
- Tumor Cells, Cultured
- Tumor Suppressor Protein p53
(metabolism)
- Y-Box-Binding Protein 1
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