NEW YORK (Reuters Health) - The adenomatous polyposis coli (APC) tumor suppressor gene exerts its control by regulating the conversion of vitamin A into retinoic acid, scientists at the University of Utah have discovered. This finding may someday translate into new treatment for patients with familial adenomatous polyposis or even colon carcinoma, which are often characterized by APC mutations.
“We initially observed that human adenomas and carcinomas are deficient in the biosynthetic enzymes that convert vitamin A into retinoic acid,” senior author Dr. David A. Jones said in an interview with Reuters Health.
He and his group in Salt Lake City studied zebrafish, which share many of the same genes with humans, to obtain genetic evidence that APC controls enterocyte differentiation by controlling retinoic acid production. The researchers report their findings in the Journal of Biological Chemistry, published online September 9.
Their experiments showed that knockout of either APC or zebrafish retinol dehydrogenase (zRDHB) in the embryos led to defective gut cell morphology in the larvae. The cells expressed neither the enterocyte differentiation marker I-FABP nor the gene hoxc8, and differentiated columnar epithelial cells failed to develop.
“If we knocked out APC in fish embryos and then treated with retinoic acid to bypass the defect, we restored within fish the normal developmental features within the gut,” Dr. Jones stated. This included restoration of I-FABP and hoxc8 levels, and some development of columnar cells, though their differentiation was not fully restored. Treatment of the zRDHB knockout fish with Hoxc8 also restored I-FABP expression.
“Taken together, the existing data raise the possibility of preventing colon adenoma formation through pharmacologic restoration of retinoid activity,” the authors conclude.
Dr. Jones noted that retinoic acid analogs have been approved by the US FDA for use in humans. He hopes to take his group’s findings into clinical trials, administering retinoic acid to patients with adenomatous polyposis in order to prevent the formation of polyps.
Source: J Biol Chem 2004. [ Google search on this article ]
MeSH Headings:Cyprinidae: Cypriniformes: Genes, Homeobox: Zebrafish: Genes, APCCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
