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Colon carcinogenesis is a multistage process involving genetic alterations of various tumor suppressor genes and oncogenes. Repressor element 1 silencing factor (REST ), which was originally discovered as a transcriptional repressor of neuronal genes, plays an important role in neuronal differentiation. In a previous genetic screening for tumor suppressor genes in human cancers, REST was identified as a candidate tumor suppressor gene in colorectal carcinogenesis. However, the role of Rest in colon carcinogenesis in vivo remains unclear because of the embryonic lethal phenotype of the conventional Rest knockout mouse. In the present study, we conditionally deleted the Rest gene in the intestinal epithelium and investigated the effect of Rest ablation in mouse colon tumorigenesis. A conditional ablation of Rest in the colonic crypts led to a rapid upregulation of Rest-targeted genes, such as Syt4, Bdnf, and Tubb3, suggesting that Rest actually suppresses the expression of its target genes in the colon. However, Rest ablation did not lead to any significant effect on the development of colon tumors in two independent mouse models of colon carcinogenesis. In addition, despite the upregulation of neuronal genes in the colonic crypts, no neuronal differentiation was observed in the colonic crypts and tumors after the Rest ablation. These results indicate that the loss of Rest expression by itself does not promote the development of colon tumors in mice, and suggest that REST may exert a tumor suppressing activity in conjunction with the additional genetic/epigenetic abnormalities that occur during colon carcinogenesis. (Cancer Sci 2011; 102: 1659–1664)