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The secreted glycoprotein CREG enhances differentiation of NTERA-2 human embryonal carcinoma cells

Oncogene volume 19, pages 2120–2128 (2000)Cite this article

Abstract

Differentiation of the human embryonal carcinoma cell line NTERA-2 is characterized by changes in morphology, altered patterns of gene expression, reduced proliferative potential, and a loss of tumorigenicity. The cellular repressor of E1A-stimulated genes, CREG, was previously shown to antagonize transcriptional activation and cellular transformation by the Adenovirus E1A oncoprotein. These properties suggested that CREG may function to inhibit cell growth and/or promote differentiation. Here we show that CREG is a secreted glycoprotein which enhances differentiation of NTERA-2 cells. Northern blot analysis reveals that, although CREG mRNA is widely expressed in adult tissues, CREG mRNA is not significantly expressed in pluripotent mouse embryonic stem cells or NTERA-2 embryonal carcinoma cells. CREG mRNA is rapidly induced upon in vitro differentiation of both mouse embryonic stem cells and human NTERA-2 cells. We show that constitutive expression of CREG in NTERA-2 cells enhances neuronal differentiation upon treatment with retinoic acid. Media enriched in CREG was also found to promote NTERA-2 differentiation in the absence of an inducer such as retinoic acid. These studies suggest that secreted CREG protein participates in a signaling cascade important for differentiation of pluripotent stem cells such as those found in teratocarcinomas.

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Acknowledgements

We thank Catherine Porcher for help with ES cell growth and differentiation, Sutisak Kitareewan and Ethan Dmitrovsky for advice on FACs analysis of NTERA-2 differentiation, and Domenic Totorella and Hidde Ploegh for help with the microsome experiments. ES cells were a kind gift of Catherine Porcher and Stuart Orkin. Ethan Dmitrovsky and Stuart Orkin provided cDNA probes. We also thank Keith Blackwell, Azad Bonni, Karl Munger and Yang Shi for helpful comments on the manuscript. R Groisman was supported by a postdoctoral fellowship from Association pour le Recherche sur le Cancer. This work was supported by grants from the Jessie B Cox Charitable Trust/The Medical Foundation and the National Institutes of Health to G Gill.

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  1. Elizabeth Veal

    Present address: School of Biochemistry and Genetics, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, UK

  2. Elizabeth Veal, Regina Groisman and Michael Eisenstein: E Veal and R Groisman have made equal contributions to the work

Authors and Affiliations

  1. Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, 02115, Massachusetts, MA, USA

    Elizabeth Veal, Regina Groisman, Michael Eisenstein & Grace Gill

  2. Dana Farber Cancer Institute, 44 Binney Street, Boston, 02115, MA, USA

    Regina Groisman

  3. Rockefeller University, 1230 York Avenue, New York City, 10021, NY, USA

    Michael Eisenstein

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Veal, E., Groisman, R., Eisenstein, M. et al. The secreted glycoprotein CREG enhances differentiation of NTERA-2 human embryonal carcinoma cells. Oncogene 19, 2120–2128 (2000). https://doi.org/10.1038/sj.onc.1203529

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