Regulation of the cell cycle machinery by oncogenic ras.
The ras proto-oncogene has been implicated during the formation of tumors in vivo as well as the transformation of cell lines in culture. Conditional expression of an activated ras mutant in Balb/c-3T3 fibroblasts failed to stimulate S phase entry in the absence of plasma-derived progression factors, but did shorten the G1 interval from 12 to 6 h and abrogate the normal proliferative requirement for platelet-derived growth factor. Ras-dependent alteration of the 3T3 cell cycle was accompanied by a dramatic increase in the expression of the G1 regulatory protein, cyclin D1, while expression of cyclin E and cyclin A proteins were only weakly induced. Cyclin/cdk complexes assembled in response to ectopic ras expression in the absence of growth factor stimulation bound the cdk inhibitory factor, Kip1, and were inactive. However, plasma-stimulated regulatory pathways functioned co-operatively with the oncogenic ras molecule to decrease Kip1 levels, induce the kinase activities associated with cyclins D, E and A, and trigger the initiation of DNA replication. Our results suggest that a ras-activated signal transduction pathway may link environmental mitogenic stimuli to the cell cycle machinery via modulation of G1 cyclin expression.
Winston
J T
JT
Department of Cell Biology, Vanderbilt University, Nashville, Tennessee 37232, USA.
Coats
S R
SR
Wang
Y Z
YZ
Pledger
W J
WJ
D016475:3T3 Cells; D000818:Animals; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D016213:Cyclins / Q000235:genetics; D004247:DNA / Q000096:biosynthesis; D011905:Genes, ras; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics; D010949:Plasma / Q000502:physiology; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000032:analysis; D025521:Tumor Suppressor Proteins
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D016213:Cyclins; D008869:Microtubule-Associated Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases