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Transcriptional repression of MMP-1 by p21SNFT and reduced in vitro invasiveness of hepatocarcinoma cells

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Abstract

p21SNFT (21 kDa small nuclear factor isolated from T cells) is a human basic leucine zipper transcription factor that can repress AP-1-mediated transcription. We show here that overexpression of p21SNFT in HepG2 cells leads to repression of matrix metalloproteinase-1 by 70–80%. p21SNFT interacted with Jun at the matrix metalloproteinase-1 promoter −88 Ets/AP-1 enhancer element, where Jun is known to activate transcription via interaction with Fos and Ets proteins. When p21SNFT/Jun dimers bound the element in the presence of Ets, DNA was protected differently than when Fos was paired with Jun. The data suggest a difference in overall conformation between p21SNFT-containing and Fos-containing complexes that may be involved in the repression of matrix metalloproteinase-1 by p21SNFT. Overexpression of p21SNFT led to a reduction in invasiveness of HepG2 cells through type I collagen and reconstituted basement membrane, an effect similar to that obtained via direct immunodepletion of matrix metalloproteinase-1. The results indicate that the mechanism of repression of matrix metalloproteinase-1 by p21SNFT may be exploited in inhibiting pathological matrix remodeling during cancer progression in vivo.

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Acknowledgements

We thank Sara McBride and Tong Xu for isolation of chicken anti-p21SNFT #12 antiserum, Alicia Arroyo for technical assistance in Type I Collagen invasion assays, and Robert W Zeller and Michael Breindl for critical review of the manuscript. The pUC9pCllase II construct was kindly provided by Peter Angel, the his-Ets-1 DBD plasmid by Barbara Nikolajczyk, the Ets/AP-1CAT constructs by Richard O’Brien, and MMP-2 primers and chicken embryo fibroblast total RNA by Andreas Bader. This work was supported by AHA Predoctoral Fellowship #0215001Y and a Sigma Xi Grant-In-Aid (to KEB) and Cancer Research Program Grant 99-00542V-10051 (to KLM).

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  1. Jamie M Fritz

    Present address: Air Force Research Laboratory/HEPC, Brooks AFB, TX, 78235-5323, USA

Authors and Affiliations

  1. Department of Biology, San Diego State University, 5500 Campanile Drive, San Diego, 92182-4614, CA, USA

    Kristen E Bower, Jamie M Fritz & Kathleen L McGuire

  2. Molecular Biology Institute, San Diego State University, 5500 Campanile Drive, San Diego, 92182-4614, CA, USA

    Kristen E Bower & Jamie M Fritz

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  1. Kristen E Bower
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Correspondence to Kristen E Bower.

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Bower, K., Fritz, J. & McGuire, K. Transcriptional repression of MMP-1 by p21SNFT and reduced in vitro invasiveness of hepatocarcinoma cells. Oncogene 23, 8805–8814 (2004). https://doi.org/10.1038/sj.onc.1208109

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