TIMP-1 regulates cell proliferation by interacting with the ninth zinc finger domain of PLZF.
The tissue inhibitors of metalloproteinases (TIMPs) are multifunctional proteins that specifically inhibit matrix metalloproteinases (MMPs) and regulate extracellular matrix (ECM) turnover and tissue remodeling. This is directed by forming tightly bound inhibitory complexes with MMPs. Recent years have revealed important differences of various biological activities between TIMP families but molecular ... mechanisms are not clear. To define the molecular mechanisms of TIMP-1-dependent biological processes, we used TIMP-1 as bait in a yeast two-hybrid screen, along with a human ovary cDNA library. Further characterization revealed the ninth zinc finger domain as an interacting domain of the promyelocytic leukemia zinc finger protein (PLZF). Interaction of PLZF with TIMP-1 in mammalian cells was also confirmed by co-immunoprecipitation and with in vitro binding assays. We investigated whether TIMP-1-mediated anti-apoptotic activity could promote the growth of ovarian cancer in an experimental model system. TIMP-1 treatment was found to be more effective at increasing ovarian cancer growth when compared with PLZF in parallel experiments. Subsequently, the efficacy of a combined treatment with TIMP-1 and PLZF was investigated. In the presence of both of these proteins, TIMP-1 significantly reduced apoptosis induced by PLZF in cervical carcinoma cells. These combined results indicate that TIMP-1 functions as an anti-activator of the transcriptional repressive activity of PLZF.
Mesh Terms:
Apoptosis, Caspase 3, Cell Proliferation, DNA, Complementary, Drug Therapy, Combination, Electrophoretic Mobility Shift Assay, Female, Gene Deletion, Gene Expression Regulation, Neoplastic, Gene Library, Genes, Reporter, HeLa Cells, Humans, Kruppel-Like Transcription Factors, Luciferases, Neoplasm Proteins, Neoplasms, Experimental, Nuclear Proteins, Ovary, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, RNA, Small Interfering, Tissue Inhibitor of Metalloproteinase-1, Transcription Factors, Transcription, Genetic, Tumor Suppressor Proteins, Two-Hybrid System Techniques, Uterine Cervical Neoplasms, Zinc Fingers
Apoptosis, Caspase 3, Cell Proliferation, DNA, Complementary, Drug Therapy, Combination, Electrophoretic Mobility Shift Assay, Female, Gene Deletion, Gene Expression Regulation, Neoplastic, Gene Library, Genes, Reporter, HeLa Cells, Humans, Kruppel-Like Transcription Factors, Luciferases, Neoplasm Proteins, Neoplasms, Experimental, Nuclear Proteins, Ovary, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, RNA, Small Interfering, Tissue Inhibitor of Metalloproteinase-1, Transcription Factors, Transcription, Genetic, Tumor Suppressor Proteins, Two-Hybrid System Techniques, Uterine Cervical Neoplasms, Zinc Fingers
J. Cell. Biochem.
Date: May. 01, 2007
PubMed ID: 17340613
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