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Identification of a New P-glycoprotein-like ATP-binding Cassette Transporter Gene That Is Overexpressed during Hepatocarcinogenesis¹

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105 [K. N. F., D. S., E. G. S., J. D. S.]; Department of Pediatrics, University of Tennessee-Memphis, Memphis, Tennessee 38101 [K. N. F.]; and Department of Medical Biophysics, The Ontario Cancer Institute, University of Toronto, Toronto, Ontario, M4X 1K9 Canada [G. B.]

The liver is remarkably insensitive to a variety of cytotoxins and expresses a number of known drug resistance genes. To isolate new P-glycoprotein (Pgp)-related genes, we screened a normal rat liver cDNA library at low stringency with a MDRI cDNA fragment containing the P-loop and ATP binding site. We isolated a novel cDNA closely related to the Pgps that is dramatically increased in hepatic neoplasia and refer to it as P-glycoprotein-related protein (PRP). The predicted protein shows PRP to be a member of the ATP-Binding Cassette (ABC) family of proteins, and a multisequence comparison of the nucleotide binding domain and the ABC family signature sequences reveals that PRP sequences are highly conserved with the greatest similarity to the yeast heavy metal transporter encoded by htm1. However, the hydropathy plot analysis suggests that PRP does not have any prominent membrane-spanning domains and thus is not typical of ABC transporters. The PRP transcript is detected in many normal tissues. In the H35 hepatoma cell line, PRP was overexpressed compared to normal liver. Southern blot analysis of DNA from the H35 rat hepatoma cells reveals that the PRP gene was amplified compared to normal liver. The orotic acid model of hepatocarcinogenesis was used to determine if during stepwise progression to liver cancer, PRP changed with hepatocarcinogenesis. At the hyperplastic nodule stage, PRP expression was increased over its expression in normal surrounding liver. More dramatic increases in PRP expression were found in frank hepatic carcinomas. Cumulatively, these studies are the first to link a novel ABC family member to the hepatic neoplastic process, a role that may be recapitulated in other cells, considering the ubiquitous expression of PRP.

¹ This work was supported in part by National Institute of Environmental Health Sciences Grants ES05851 (to J. D. S.) and ES04628 (to E. G. S.), by NIH grant CA63230 and NIH/NCI Cancer Center Support (CORE) Grant CA21765, by the Duncan L. Gordon Fellowship from The Hospital for Sick Children Foundation, Toronto, Ontario, Canada (to K. N. F.), by a Center of Excellence Grant from the State of Tennessee (to K. N. F.), and by funds from the American Lebanese Syrian Associated Charities.

² Present address: Division of Gastroenterology and Nutrition, The Hospital for Sick Children, The University of Toronto, 555 University Avenue, Toronto, Ontario, M5G 1X8 Canada.

³ To whom requests for reprints should be addressed, at Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 North Lauderdale Avenue, Memphis, TN 38105. Phone: (901) 495-2174; Fax: (901) 525-6869; E-mail: john.schuetz@stjude.org.

Received 10/ 2/96. Accepted 7/ 1/97.

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