Activation of c-Myc uncouples DNA replication from activation of G1-cyclin-dependent kinases

• Published in: Oncogene Vol. 15; no. 6; pp. 649 - 656
• Main Authors: PUSCH, O, BERNASCHEK, G, EILERS, M, HENGSTSCHLÄGER, M
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 07.08.1997; Nature Publishing Group
• Subjects: Animals; Biological and medical sciences; c-Myc protein; Cancer; Carrier Proteins; Cell activation; Cell cycle; Cell Cycle - genetics; Cell Cycle - physiology; Cell Cycle Proteins; Cell cycle, cell proliferation; Cell physiology; Cell size; Cell Size - genetics; Centrifugation; Cyclin A; Cyclin E; Cyclin-dependent kinase 2; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-dependent kinases; Cyclin-Dependent Kinases - metabolism; Cyclins - analysis; Cyclins - metabolism; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA Replication - genetics; DNA-Binding Proteins; E2F protein; E2F Transcription Factors; Fibroblasts; Flow Cytometry; Fundamental and applied biological sciences. Psychology; G1 Phase - genetics; Genes, myc - physiology; Microtubule-Associated Proteins - metabolism; Mitosis; Mitosis - genetics; Molecular and cellular biology; Myc protein; Phosphorylation; Proto-oncogenes; Rats; Replication; Retina; Retinoblastoma; Retinoblastoma protein; Retinoblastoma Protein - metabolism; Retinoblastoma-Binding Protein 1; Transcription Factor DP1; Transcription Factors - metabolism; Tumor Cells, Cultured; Tumor Suppressor Proteins; Yeast; Rat; Rodentia; Cyclin; Activation; Gene expression; Vertebrata; G1 Phase; Regulation(control); Mammalia; Cell line; DNA; C-Onc gene; Cell cycle; Replication; Transcription factor
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1201236

Proto-oncogenes like c-myc are thought to control exit from the cell cycle rather than progression through the cell cycle itself. We now present a different view of Myc function. Exponentially growing Rat1-MycER fibroblasts were size-fractionated by centrifugal elutriation. In these cells, activation of cyclin E- and cyclin A-dependent kinases, degradation of p27, hyperphosphorylation of retinoblastoma protein and activation of E2F occur sequentially at specific cell sizes. Upon activation of Myc, however, these transitions all occur simultaneously in small cells immediately after exit from mitosis. In contrast, Myc has no discernible effect on the cell size at which DNA replication is initiated. These data show first that Myc controls the activity of G1 cyclin-dependent kinases independently from the transition between quiescence and proliferation and from any effect on cell growth in size. These data also provide evidence of at least one dominant mechanism besides activation of E2F and of cyclin E/cdk2 kinase, which prevents DNA replication unless a critical cell size has been reached.