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J. Biol. Chem., Vol. 282, Issue 23, 17053-17060, June 8, 2007

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Critical Role for Transcription Coactivator Peroxisome Proliferator-activated Receptor (PPAR)-binding Protein/TRAP220 in Liver Regeneration and PPAR Ligand-induced Liver Tumor Development^*

Kojiro Matsumoto, Songtao Yu, Yuzhi Jia, Mohamed R. Ahmed, Navin Viswakarma, Joy Sarkar, Papreddy V. Kashireddy, M. Sambasiva Rao, William Karpus, Frank J. Gonzalez, and Janardan K. Reddy¹

From the Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611-3008 and Laboratory of Metabolism, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892

Disruption of the gene encoding for the transcription coactivator peroxisome proliferator-activated receptor (PPAR)-binding protein (PBP/TRAP220/DRIP205/Med1) in the mouse results in embryonic lethality. Here, we have reported that targeted disruption of the Pbp/Pparbp gene in hepatocytes (Pbp^Liv) impairs liver regeneration with low survival after partial hepatectomy. Analysis of cell cycle progression suggests a defective exit from quiescence, reduced BrdUrd incorporation, and diminished entry into G₂/M phase in Pbp^Liv hepatocytes after partial hepatectomy. Pbp^Liv hepatocytes failed to respond to hepatocyte growth factor/scatter factor, implying that hepatic PBP deficiency affects c-met signaling. Pbp gene disruption also abolishes primary mitogen-induced liver cell proliferative response. Striking abrogation of CCl₄-induced hepatocellular proliferation and hepatotoxicity occurred in Pbp^Liv mice pretreated with phenobarbital due to lack of expression of xenobiotic metabolizing enzymes necessary for CCl₄ activation. Pbp^Liv mice, chronically exposed to Wy-14,643, a PPAR ligand, revealed a striking proliferative response and clonal expansion of a few Pbp^fl/fl hepatocytes that escaped Cre-mediated gene deletion in Pbp^Liv livers, but no proliferative expansion of PBP null hepatocytes was observed. In these Pbp^Liv mice, none of the Wy-14,643-induced hepatic adenomas and hepatocellular carcinomas was derived from PBP^Liv hepatocytes; all liver tumors developing in Pbp^Liv mice maintained non-recombinant Pbp alleles and retained PBP expression. These studies provide direct evidence in support of a critical role of PBP/TRAP220 in liver regeneration, induction of hepatotoxicity, and hepatocarcinogenesis.

Received for publication, March 7, 2007 , and in revised form, April 10, 2007.

^* This work was supported, in part, by National Institutes of Health Grants GM23750 and CA104578 (to J. K. R.) and by the Mayberry Endowment Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pathology, Northwestern University, Feinberg School of Medicine, 303 E. Chicago Ave., Chicago, IL 60611-3008. Tel.: 312-503-7948; E-mail: jkreddy{at}northwestern.edu.

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