Serum starved v-mos-transformed cells are unable to appropriately downregulate cyclins and CDKs.
Serum deprived v-mos-transformed NIH3T3 cells are unable to enter a true quiescent state, but instead, arrest in the early G1 phase of the cell cycle. We have analysed several cell cycle regulatory proteins in these G1 arrested cells and show altered regulation in the expression and activity of certain cyclins and cyclin-dependent kinases. In particular, p34cdc2, cyclin A, cyclin D and cyclin E are not appropriately down-regulated in serum starved, G1 arrested, v-mos-transformed cells as compared with quiescent NIH3T3 cells. Furthermore, serum starved v-mos-transformed cells have elevated histone H1 kinase activity associated with cyclin A, cyclin E, p33cdk2, and p34cdc2. Using a metallothionein-inducible c-mos(mu) expression system, we show that c-mos(mu) induction in quiescent NIH3T3 cells causes elevated expression of p34cdc2. However, this induction of c-mos(mu) and subsequent expression of p34cdc2 was not sufficient to promote significant entry of cells into S phase. Analysis of extracts from serum starved v-H-ras, v-src, and tpr-met transformed NIH3T3 cells demonstrates that these oncogene-transformed cells also contain elevated levels of p34cdc2. We propose that the altered regulation of these critical cell cycle regulatory molecules, and specifically the inability to fully downregulate their activity, contributes significantly to neoplastic transformation and subsequent unregulated growth of tumor cells.
Rhodes
N
N
Growth Control and Cancer Group, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Innes
C L
CL
Propst
F
F
Paules
R S
RS
D016475:3T3 Cells / Q000502:physiology / Q000821:virology; D000818:Animals; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D042846:CDC2-CDC28 Kinases; D002455:Cell Division / Q000235:genetics; D002461:Cell Line, Transformed; D016895:Culture Media, Serum-Free; D019938:Cyclin D1; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism*; D015536:Down-Regulation; D016193:G1 Phase / Q000235:genetics; D016258:Genes, mos; D008668:Metallothionein / Q000235:genetics; D051379:Mice; D015513:Oncogene Proteins / Q000378:metabolism; D009857:Oncogenes; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism
D016895:Culture Media, Serum-Free; D016213:Cyclins; D015513:Oncogene Proteins; D019938:Cyclin D1; D008668:Metallothionein; D011494:Protein Kinases; C102333:histone H1 kinase; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases