Novel function of APC
Nuclear APC mediates Wnt coregulator exchangeDr. Katherine Jones (The Salk Institute) and colleagues have uncovered a novel mechanism of Wnt transcriptional regulation, and lend new insight into the molecular genetics of colorectal cancer development.
"Studies of this new APC-regulated process could aid in the development of future inhibitors of colon cancer as well as other aggressive human cancers, including melanoma, that de-regulate the Wnt/beta-catenin signaling pathway," states Dr. Jones.
It is well established that the adenomatous polyposis coli (APC) tumor suppressor suppresses Wnt signaling by inhibiting beta-catenin, the key transcription factor that turns on Wnt target genes, like c-Myc. Until now, it was believed that APC inhibited beta-catenin by promoting its nuclear export and subsequent proteosomal degradation in the cytoplasm. Dr. Jones and colleagues now demonstrate that APC also acts in the nucleus, where it also opposes the activity of beta-catenin directly at Wnt target genes.
Their new paper reports that beta-catenin induces c-Myc expression by promoting H3K4 trimethylation of the gene, a chromatin modification that is associated with active genes and open chromatin structure. The APC tumor suppressor represses c-Myc expression by recruiting enzymes that counteract this open chromatin state, and modify beta-catenin for destruction.
Interestingly, the researchers found that only full-length APC protein, and not the truncated APC proteins that are present in human colon cancers, is capable of repressing c-Myc gene expression in the nucleus. Dr. Jones emphasizes that "Our findings indicate that the APC tumor suppressor is a transcription factor, which is able to enter the nucleus and shut off c-Myc and other Wnt target genes directly. The mutant APC proteins commonly found in human colorectal cancers are unable to do this, and consequently colon cancer cells not only fail to destroy beta-catenin, but are also unable to switch off the genes, like c-Myc, that are induced by the Wnt/beta-catenin pathway."
Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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