Genetic dissection of mammalian Cdc7 kinase: cell cycle and developmental roles.
Cdc7, originally discovered by Hartwell as a budding yeast mutant that arrests immediately before the onset of S phase, is conserved through evolution and plays essential roles in initiation of mitotic DNA replication. Inducible inactivation of Cdc7 in mouse embryonic stem cells leads to rapid cessation of DNA synthesis and the subsequent activation of checkpoint responses, resulting in p53 activation and eventually p53-mediated apoptosis. This indicates a requirement of Cdc7 kinase for ongoing replication of mammalian genomes, and loss of Cdc7 kinase presumably generates arrested replication fork signals. Cdc7-/- mice or embryonic fibroblast cells (MEFs) expressing a low level of transgene-encoded Cdc7 protein are viable but exhibit reduced body size with impaired germ cell development and decreased cell proliferation. Interestingly, these phenotypes are largely corrected by the presence of an additional copy of the transgene, resulting in increased level of Cdc7 expression. This indicates the requirement of a critical level of Cdc7 for normal cell proliferation and development of specific organs. These results from mammals will be discussed in conjunction with the pleiotropic effects of Cdc7 mutation observed in yeasts.
Kim
Jung Min
JM
Department of Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Masai
Hisao
H
D000818:Animals; D017209:Apoptosis; D049628:Body Size; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D004261:DNA Replication; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism; D008660:Metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*
D018797:Cell Cycle Proteins; C068619:CDC7 protein, human; D017346:Protein Serine-Threonine Kinases