Cdc6 requires anchorage for its expression.
Fibroblasts need anchorage to extracellular matrix to transit from G1 to S phase, but no longer after oncogenic transformation. Here we report that Cdc6 protein essential for the activation of replication origins requires anchorage or oncogenic stimulation for its execution. Upon anchorage loss, Cdc6 expression is shut off both transcriptionally and post-transcriptionally in a rat fibroblast despite enforced activation of E2F-dependent promoters. However, stimulation of this cell with oncogenic growth factors suppresses this shutoff and concurrently activates Cdk2 and Cdk6/4, thereby overriding the anchorage requirement for the G1-S transition and consequently enabling cells to perform anchorage-independent S phase entry. Analysis with enforced expression of Cdc6 indicates that the G1 cyclin-dependent kinases and Cdc6 constitute major cell cycle targets for the restriction of the G1-S transition by anchorage loss.
Jinno
Shigeki
S
Department of Biochemistry and Molecular Biology, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. jinno@m.u-tokyo.ac.jp
Yageta
Mika
M
Nagata
Akihisa
A
Okayama
Hiroto
H
D000818:Animals; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins / Q000032:analysis* / Q000235:genetics; D002460:Cell Line; D019925:Cyclin A / Q000502:physiology; D051357:Cyclin-Dependent Kinase 2; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases / Q000502:physiology; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016193:G1 Phase; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D051381:Rats; D016196:S Phase; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
C066503:CDC6 protein, S cerevisiae; D018797:Cell Cycle Proteins; D019925:Cyclin A; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495892:Cdk2 protein, rat; C495913:Cdk6 protein, rat; D051357:Cyclin-Dependent Kinase 2; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases