Increased G1 cyclin/cdk activity in cells overexpressing the candidate oncogene, MCT-1.
We have recently identified a novel candidate oncogene, MCT-1, in the HUT 78 T-cell line. When overexpressed in NIH3T3 fibroblasts, the MCT-1 gene shortens the G1 phase of the cell cycle and promotes anchorage-independent growth. Progression of cells through a late G1 phase restriction point is regulated by G1 cyclins whose phosphorylation of the retinoblastoma gene product facilitates entry into S phase. Deregulated expression of G1 cyclins and their cognate cdk partners is often found in human tumor cells. In order to address the potential relationship of MCT-1 to cell cycle regulatory molecules, we analyzed the ability of MCT-1 overexpression to modulate cdk4 and cdk6 kinase activity in NIH3T3 fibroblasts constitutively overexpressing MCT-1. We observed an increase in the kinase activity of both cdk4 and cdk6 in asynchronously growing transformed cells compared with the parent cells. This increased kinase activity was accompanied by an elevated level of cyclin D1 protein and increased G1 cyclin/cdk complex formation. We also observed a correlation between increased protein levels of MCT-1 with cyclin D1 expression in a panel of lymphoid cell lines derived from T-cell malignancies. These results demonstrate that constitutive expression of MCT-1 is associated with deregulation of protein kinase-mediated G1 phase checkpoints.
Dierov
J
J
Center for NeuroVirology and NeuroOncology, MCP Hanhemann School of Medicine, Philadelphia, Pennsylvania 19102, USA.
Prosniak
M
M
Gallia
G
G
Gartenhaus
R B
RB
D016475:3T3 Cells; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D019938:Cyclin D1 / Q000378:metabolism; D056746:Cyclin G; D056766:Cyclin G1; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism*; D016193:G1 Phase / Q000502:physiology; D015870:Gene Expression; D006801:Humans; D051379:Mice; D015513:Oncogene Proteins / Q000235:genetics*; D009857:Oncogenes; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D014162:Transfection
C534702:CCNG1 protein, human; C493956:CDKN1A protein, human; C534703:Ccng1 protein, mouse; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D056746:Cyclin G; D056766:Cyclin G1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; C115081:MCTS1 protein, human; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D019938:Cyclin D1; D017346:Protein Serine-Threonine Kinases; C495900:CDK4 protein, human; C495911:CDK6 protein, human; C495902:Cdk4 protein, mouse; C495912:Cdk6 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases