| Summary: | 博士 === 國防醫學院 === 生命科學研究所 === 88 === Retinoids, derivatives of vitamin A exert wide spectrum antitumor activities that are mediated through induction of growth arrest, differentiation or apoptosis. The compounds are active in preventing the development of gastric cancer, and the decrease in serum vitamin A levels is associated with an increase in risk of gastric cancer. Our previous studies have found that All-trans retinoic acid (tRA) induced growth inhibition of SC-M1 gastric cancer cells, which was associated with the G0/G1 arrest. Also, SC-M1 cells became flattened and enlarged following tRA treatment. To determine whether effects of retinoids are mediated by specific gene activation or repression, SC-M1 CL23 cells treated with vehicle alone or tRA (10 mM) for one day were analyzed using the technique of differential display. Two tRA positively regulated genes were identified. One was a novel gene named as retinoid inducible-gene 1 (RIG1) and the other was the calcium binding protein S100P that belongs to the S100 family. The full-length RIG1 cDNA contained 768 base pairs and encoded 164 amino acids with a protein molecular weight of 18 kDa. The RIG1 gene, localized at chromosome 11q, was ubiquitously expressed in normal tissues, and its expression was positively associated with cellular density. The RIG1 gene was regulated by retinoids through RXR/RAR heterodimers, and the regulation of RIG1 was related to cellular retinoid sensitivity. Nucleotide sequence analysis demonstrated that cDNA of the RIG1 gene was 98.8% homologous to that of the TIG3 gene and had 54% nucleotide sequence homology to a type II tumor suppressor gene H-REV107-1. The RIG1 protein has one consensus sequence motifs DXXG, which is conserved between different guanosine nucleotide-binding proteins. Overexpression of RIG1-myc-his and RIG1-EGFP fusion proteins resulted growth arrest or cellular apoptosis, which is cell dependent. Also, transient expression of RIG1 fusion proteins suppressed ELK-1, JUN and CHOP signal pathways of HtTA cells. tRA upregulated S100P expression in RA-sensitive SC-M1 CL23 and HtTA cells. The regulation was maintained in resistance cells induced by long term treatment with tRA. The genuine roles of RIG1 and S100P in tRA-mediated growth suppression or cellular differentiation require further study.
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