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TIS21 negatively regulates hepatocarcinogenesis by disruption of cyclin B1-Forkhead box M1 regulation loop.

Authors
Park, TJ; Kim, JY; Oh, SP; Kang, SY; Kim, BW; Wang, HJ; Song, KY; Kim, HC; Lim, IK
Citation
Hepatology (Baltimore, Md.), 47(5):1533-1543, 2008
Journal Title
Hepatology (Baltimore, Md.)
ISSN
0270-91391527-3350
Abstract
A functional and biochemical interaction of TIS21(/BTG2/PC3) with Forkhead box M1 (FoxM1), essential transcription factor for hepatocyte regeneration and a master regulator of mitotic gene expression, was explored. Growth of hepatocellular carcinoma (HCC), developed by a single injection of diethylnitrosamine (DEN), was the same in both the TIS21(+/+) and TIS21(-/-) mice until 6 months, whereas it was significantly higher in the TIS21(-/-) mice at 9 months. Expression of TIS21 was significantly lower in both human and murine HCCs than in the surrounding tissues. Forced expression of TIS21 impaired growth, proliferation, and tumorigenic potential of Huh7 cells. At the mechanistic level, TIS21 inhibited FoxM1 phosphorylation, a required modification for its activation, by reducing cyclin B1-cdk1 activity, examined by in vitro kinase assay and FoxM1 mutant analyses. These observations were further confirmed in vivo by the reciprocal control of TIS21 expression and FoxM1 phosphorylation in the diethylnitrosamine-induced HCCs and TIS21(-/-) mouse embryonic fibroblast (MEF), in addition to increased expression of cyclin B1 and cdk1 activity. CONCLUSION: TIS21 negatively regulated hepatocarcinogenesis in part by disruption of the FoxM1-cyclin B1 regulatory loop, thereby inhibiting proliferation of transformed cells developed in mouse and human livers.
MeSH terms
AnimalsCarcinoma, Hepatocellular/chemically inducedCarcinoma, Hepatocellular/genetics*Carcinoma, Hepatocellular/pathologyCell Cycle Proteins/geneticsCell DivisionCell Line, TumorCyclin B/geneticsCyclin B1DiethylnitrosamineForkhead Transcription Factors/genetics*Gene Expression Regulation, Neoplastic*Genes, Tumor SuppressorHumansImmediate-Early Proteins/genetics*Liver Neoplasms/chemically inducedLiver Neoplasms/genetics*Liver Neoplasms/pathologyMiceMice, TransgenicMutagenesis, Site-DirectedPromoter Regions, GeneticTumor Suppressor Proteins
DOI
10.1002/hep.22212
PMID
18393292
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
Journal Papers > School of Medicine / Graduate School of Medicine > Surgery
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