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

Sarah J. Freemantle, Joanna S. Kerley, Shannon L. Olsen, Robert H. Gross, Michael J. Spinella

Research output: Contribution to journalArticlepeer-review

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 micro-arrays 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.

Original languageEnglish (US)
Pages (from-to)2880-2889
Number of pages10
JournalOncogene
Volume21
Issue number18
DOIs
StatePublished - 2002
Externally publishedYes

Keywords

  • Development
  • Differentiation
  • Embryonal carcinoma
  • Mammalian embryogenesis
  • Microarray
  • Retinoic acid

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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