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


CONCLUSIONS
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.
Park
Tae Jun
TJ
Department of Biochemistry and Molecular Biology, Ajou University, School of Medicine, Suwon, Republic of Korea.
Kim
Ji Yeon
JY
Oh
S Paul
SP
Kang
So Young
SY
Kim
Bong Wan
BW
Wang
Hee Jung
HJ
Song
Kye Yong
KY
Kim
Hyoung Chin
HC
Lim
In Kyoung
IK
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics; D002455:Cell Division; D045744:Cell Line, Tumor; D019926:Cyclin B / Q000235:genetics; D056744:Cyclin B1; D004052:Diethylnitrosamine; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics*; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic; D025521:Tumor Suppressor Proteins
C489435:Btg2 protein, mouse; C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse; D018797:Cell Cycle Proteins; D019926:Cyclin B; D056744:Cyclin B1; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D017874:Immediate-Early Proteins; D025521:Tumor Suppressor Proteins; C070114:BTG2 protein, human; D004052:Diethylnitrosamine