Differential control of cyclins D1 and D3 and the cdk inhibitor p27Kip1 by diverse signalling pathways in Swiss 3T3 cells.
Quiescent Swiss 3T3 cells can be induced to re-enter the cell cycle by stimulation of a variety of growth factor-dependent signal transduction cascades. We have utilised this cell system to investigate the point of convergence of mitogenic signalling by analysing the changes that distinct mitogens induce in the components of the cell cycle regulatory machinery (the G1 cyclins, cdks and their inhibitors). In the presence of insulin, activation of cAMP-dependent protein kinase caused a dramatic post-transcriptional down-regulation of p27(Kip1), an increase in cyclin D3 but had little effect on cyclin D1 levels, whilst activation of protein kinase C had a more modest effect on cyclin D3 and p27(Kip1) but caused a striking elevation in the expression of cyclin D1. The neuropeptide bombesin, when combined with insulin, caused increased expression of cyclin D1 and down-regulation of p27(Kip1) mRNA and protein. Thus each combination of mitogenic agents had different effects on the components responsible for regulating the orderly progression of the cell cycle. This outcome is incompatible with a single route to mitogenesis and demonstrates that different mitogens remain distinct in the signalling responses they initiate, only converging at the levels of the expression of the D-type cyclins and the inhibitor p27(Kip1).
Mann
D J
DJ
Gene Regulation Laboratory, Imperial Cancer Research Fund, London.
Higgins
T
T
Jones
N C
NC
Rozengurt
E
E
D016475:3T3 Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D019938:Cyclin D1; D056743:Cyclin D3; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000502:physiology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000502:physiology*; D008934:Mitogens / Q000494:pharmacology*; D015513:Oncogene Proteins / Q000502:physiology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013268:Stimulation, Chemical; D025521:Tumor Suppressor Proteins
C534697:Ccnd3 protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D056743:Cyclin D3; D016213:Cyclins; D008869:Microtubule-Associated Proteins; D008934:Mitogens; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases