Developmentally-related candidate retinoic acid target genes regulated early during neuronal differentiation of human embryonal carcinoma.
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-beta (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.
Freemantle
Sarah J
SJ
The Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire, NH 03755, USA.
Kerley
Joanna S
JS
Olsen
Shannon L
SL
Gross
Robert H
RH
Spinella
Michael J
MJ
D018236:Carcinoma, Embryonal; D002454:Cell Differentiation; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D014212:Tretinoin