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J. Biol. Chem., Vol. 277, Issue 28, 24875-24882, July 12, 2002

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Combinatorial Interactions of p53, Activating Protein-2, and YB-1 with a Single Enhancer Element Regulate Gelatinase A Expression in Neoplastic Cells^*

Peter R. Mertens^§¶, Karin Steinmann^¶, Maria A. Alfonso-Jaume, Abdelaziz En-Nia, Yi Sun^**, and David H. Lovett

From the  Department of Nephrology and Immunology, Medical Clinic II, RWTH Aachen, Pauwelsstraße 30, 52057 Aachen, Germany, the  Department of Medicine, San Francisco Veterans Affairs Medical Center/University of California, San Francisco, California, and ^** Cancer Molecular Sciences, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, Michigan 48105

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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