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PMID:17438330

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Citation

Matsumoto, K, Yu, S, Jia, Y, Ahmed, MR, Viswakarma, N, Sarkar, J, Kashireddy, PV, Rao, MS, Karpus, W, Gonzalez, FJ and Reddy, JK (2007) Critical role for transcription coactivator peroxisome proliferator-activated receptor (PPAR)-binding protein/TRAP220 in liver regeneration and PPARalpha ligand-induced liver tumor development. J. Biol. Chem. 282:17053-60

Abstract

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(DeltaLiv)) 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 G(2)/M phase in Pbp(DeltaLiv) hepatocytes after partial hepatectomy. Pbp(DeltaLiv) 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 CCl(4)-induced hepatocellular proliferation and hepatotoxicity occurred in Pbp(DeltaLiv) mice pretreated with phenobarbital due to lack of expression of xenobiotic metabolizing enzymes necessary for CCl(4) activation. Pbp(DeltaLiv) mice, chronically exposed to Wy-14,643, a PPARalpha ligand, revealed a striking proliferative response and clonal expansion of a few Pbp(fl/fl) hepatocytes that escaped Cre-mediated gene deletion in Pbp(DeltaLiv) livers, but no proliferative expansion of PBP null hepatocytes was observed. In these Pbp(DeltaLiv) mice, none of the Wy-14,643-induced hepatic adenomas and hepatocellular carcinomas was derived from PBP(DeltaLiv) hepatocytes; all liver tumors developing in Pbp(DeltaLiv) 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.

Links

PubMed Online version:10.1074/jbc.M701956200

Keywords

Animals; Base Sequence; DNA Primers; Hepatectomy; Ligands; Liver Neoplasms, Experimental/pathology; Liver Neoplasms, Experimental/physiopathology; Liver Regeneration/physiology; Mediator Complex Subunit 1; Mice; PPAR alpha/metabolism; Transcription Factors/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:MED1

acts_upstream_of_or_within

GO:0031100: animal organ regeneration

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2176946,MGI:MGI:3511276

P

  • occurs_in:(EMAPA:16846)

Seeded From UniProt

complete

MOUSE:MED1

acts_upstream_of_or_within

GO:2000347: positive regulation of hepatocyte proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2176946,MGI:MGI:3511276

P

Seeded From UniProt

complete

MOUSE:MED1

acts_upstream_of_or_within

GO:0070318: positive regulation of G0 to G1 transition

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2176946,MGI:MGI:3511276

P

  • regulates_o_occurs_in:(EMAPA:16846)

Seeded From UniProt

complete

MOUSE:MED1

acts_upstream_of_or_within

GO:0035729: cellular response to hepatocyte growth factor stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2176946,MGI:MGI:3511276

P

Seeded From UniProt

complete


See also

References

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