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Inhibition of tumor growth and metastasis of human melanoma by intracellular anti-ATF-1 single chain Fv fragment

Oncogene volume 19, pages 2721–2730 (2000)Cite this article

Abstract

Activating transcription factor-1 (ATF-1) and cAMP-responsive element (CRE)-binding protein (CREB) have been implicated in cAMP and Ca2+-induced transcriptional activation. The expression of the transcription factors CREB and ATF-1 is upregulated in metastatic melanoma cells. However, how overexpression of ATF-1/CREB contributes to the acquisition of the metastatic phenotype remains unclear. Here, the effect of disrupting ATF-1 activity was investigated using intracellular expression of an inhibitory anti-ATF-1 single chain antibody fragment (ScFv). Intracellular expression of ScFv anti-ATF-1 in MeWo melanoma cells caused significant reduction in CRE-dependent promoter activation. In addition, expression of ScFv anti-ATF-1 in melanoma cells suppressed their tumorigenicity and metastatic potential in nude mice. ScFv anti-ATF-1 rendered the melanoma cells susceptible to thapsigargin-induced apoptosis in vitro and caused massive apoptosis in tumors transplanted subcutaneously into nude mice, suggesting that ATF-1 and its associated proteins act as survival factor for human melanoma cells. This is the first report to demonstrate the potential of ScFv anti-ATF-1 as an inhibitor of tumor growth and metastasis of solid tumor in vivo.

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Acknowledgements

We thank Dr MR Montiminy for the gift of the CRE-dependent promoter-CAT vector, Dr MR Green for the antibody against ATF-1, Dr RH Goodman for the KCREB expression vector, and Patherine Greenwood for expert preparation of this manuscript. Supported in part by NIH grant CA76098 (to M Bar-Eli).

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Authors and Affiliations

  1. Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, Texas, TX, USA

    Didier Jean, Carmen Tellez, Suyun Huang, Darren W Davis, Christiane J Bruns, David J McConkey & Menashe Bar-Eli

  2. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, 68198, Nebraska, NE, USA

    Steven H Hinrichs

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  1. Didier Jean
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Jean, D., Tellez, C., Huang, S. et al. Inhibition of tumor growth and metastasis of human melanoma by intracellular anti-ATF-1 single chain Fv fragment. Oncogene 19, 2721–2730 (2000). https://doi.org/10.1038/sj.onc.1203569

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