Loss of protooncogene c-Myc function impedes G1 phase progression both before and after the restriction point.
c-myc is an important protooncogene whose misregulation is believed to causally affect the development of numerous human cancers. c-myc null rat fibroblasts are viable but display a severe (two- to threefold) retardation of proliferation. The rates of RNA and protein synthesis are reduced by approximately the same factor, whereas cell size remains unaffected. We have performed a detailed kinetic cell cycle analysis of c-myc(-/-) cells by using several labeling and synchronization methods. The majority of cells (>90%) in asynchronous, exponential phase c-myc(-/-) cultures cycle continuously with uniformly elongated cell cycles. Cell cycle elongation is due to a major lengthening of G(1) phase (four- to fivefold) and a more limited lengthening of G(2) phase (twofold), whereas S phase duration is largely unaffected. Progression from mitosis to the G1 restriction point and the subsequent progression from the restriction point into S phase are both drastically delayed. These results are best explained by a model in which c-Myc directly affects cell growth (accumulation of mass) and cell proliferation (the cell cycle machinery) by independent pathways.
Schorl
Christoph
C
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912, USA.
Sedivy
John M
JM
D000818:Animals; D000963:Antimetabolites / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005434:Flow Cytometry; D016193:G1 Phase / Q000502:physiology*; D016259:Genes, myc; D006801:Humans; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013997:Time Factors
D000963:Antimetabolites; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D001973:Bromodeoxyuridine