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Developmentally-related candidate retinoic acid target genes regulated early during neuronal differentiation of human embryonal carcinoma

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Abstract

Embryonal carcinoma is a model of embryonic development as well as tumor cell differentiation. In response to all-trans retinoic acid (RA), the human embryonal carcinoma (EC) cell line, NT2/D1, differentiates toward a neuronal lineage with associated loss of cell growth and tumorigenicity. Through the use of cDNA-based microarrays we sought to identify the early downstream targets of RA during differentiation commitment of NT2/D1 cells. A total of 57 genes were induced and 37 genes repressed by RA. RA regulated genes were restricted at 8 h with 27 genes induced and five repressed. The total number of RA-responsive transcripts increased at 24 and 48 h and their pattern of expression was more symmetrical. For a given time point less than 1% of the 9128 cDNAs on the expression array were regulated by RA. Many of these gene products are associated with developmental pathways including those of TGF-β (Lefty A, NMA, follistatin), homeo domain (HoxD1, Meis2, Meis1, Gbx2), IGF (IGFBP3, IGFBP6, CTGF), Notch (manic fringe, ADAM11), Hedgehog (patched) and Wnt (Frat2, secreted frizzled-related protein 1) signaling. In addition a large cassette of genes induced by RA at 24–48 h are associated with cell adhesion, cytoskeletal and matrix remodeling, growth suppression and intracellular signaling cascades. The majority of repressed genes are associated with protein/RNA processing, turnover or metabolism. The early induced genes identified may play a regulatory role in RA-mediated growth suppression and terminal differentiation and may have physiologic or pharmacologic importance during normal human development and retinoid-based cancer therapy or prevention.

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Acknowledgements

We thank Dr Ethan Dmitrovsky (Dartmouth Medical School) for helpful discussion. This work was supported by the National Cancer Institute Howard Temin Award K01-CA75154 (MJ Spinella), by American Cancer Society Research Scholar Grant RSG-01-144-01 (MJ Spinella) and by a grant from the Lance Armstrong Foundation (SJ Freemantle).

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  1. Sarah J Freemantle and Joanna S Kerley: SJ Freemantle and JS Kerley contributed equally to this work

Authors and Affiliations

  1. The Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, 03755, New Hampshire, NH, USA

    Sarah J Freemantle, Joanna S Kerley, Shannon L Olsen & Michael J Spinella

  2. The Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Lebanon, 03755, New Hampshire, NH, USA

    Sarah J Freemantle, Joanna S Kerley, Shannon L Olsen & Michael J Spinella

  3. The Department of Biological Sciences, Dartmouth College, Hanover, 03755, New Hampshire, NH, USA

    Robert H Gross

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  1. Sarah J Freemantle
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  2. Joanna S Kerley
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Correspondence to Michael J Spinella.

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Freemantle, S., Kerley, J., Olsen, S. et al. Developmentally-related candidate retinoic acid target genes regulated early during neuronal differentiation of human embryonal carcinoma. Oncogene 21, 2880–2889 (2002). https://doi.org/10.1038/sj.onc.1205408

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