Extracellular signal-regulated kinase induces cyclin D1 and Cdk-2 expression and phosphorylation of retinoblastoma in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is one of the most common malignancies in Southeast Asia. Hyperphosphorylation of retinoblastoma (pRB) by cyclin/CDKs in G1/S transition is required for its inactivation and cell cycle progression. In the present study, we report that phosphorylation of pRB at Ser780 and Ser795 was detected in 71% (33 of 46) and 63% (29 of 46) of HCCs examined respectively. pRB protein was undetectable in 13% (6 of 46) of HCCs examined. Phosphorylated pRB was localized in the nuclei of hepatocarcinoma cells. Benign hepatocytes exhibited very weakly or no nuclear staining for phosphorylated pRB. Over-expression of E2F-1, cyclin D1, Cdk-2, Cdk-4 and cyclin A was found in 64% (30 of 46), 43% (26 of 46), 28% (11 of 46), 71% (33 of 46) and 63% (29 of 46) of HCCs examined respectively and this was correlated with elevation of ERK. Treatment of HepG2 cells with MEK1/2 inhibitor U0126 resulted in cell cycle arrest, downregulation of cyclin D1 and Cdk-2 expression and inhibition of pRB phosphorylation at Ser780 and Ser795. Ectopic expression of activated MEK1 in HepG2 cells increased cyclin D1 and Cdk-2 expression, phosphorylation of pRB at Ser780 and Ser795, and percentage of cells in S phase. Our data indicate that activated ERK plays an important role in cyclin D1 and Cdk-2 expression and phosphorylation of pRB at Ser780 and Ser795 in liver cancer cells.
Huynh
H
H
Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre of Singapore, 169610, Singapore. cmrhth@nccs.com.sg
Do
P T
PT
Nguyen
T H
TH
Chow
P
P
Tan
P H
PH
Quach
T H
TH
Van
T
T
Soo
K C
KC
Tran
E
E
D042846:CDC2-CDC28 Kinases / Q000096:biosynthesis*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D019938:Cyclin D1 / Q000096:biosynthesis*; D051357:Cyclin-Dependent Kinase 2; D048049:Extracellular Signal-Regulated MAP Kinases / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D014407:Tumor Cells, Cultured
D016160:Retinoblastoma Protein; D019938:Cyclin D1; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D048049:Extracellular Signal-Regulated MAP Kinases