MYC can enforce cell cycle transit from G1 to S and G2 to S, but not mitotic cellular division, independent of p27-mediated inihibition of cyclin E/CDK2.
Overexpression of the MYC proto-oncogene exerts protean biological effects that may contribute to its ability to induce tumorigenesis including enforcing cellular growth and proliferation and inducing genomic instability. MYC overexpression may induce genomic damage at least in part by causing inappropriate DNA replication. MYC may induce inappropriate DNA replication through the activation of Cyclin E/CDK2. To address this possibility, the effects of ectopic p27 expression in immortal rat fibroblasts or human breast epithelial cell lines on MYC-induced endo-reduplication was determined. p27 inhibited Cyclin E/CDK2 associated kinase activity, but failed to prevent MYC from inducing transit from G1 to S phase; inhibited at lower but not higher levels of MYC transit from G2 to S and endo-reduplication; however, MYC failed to enforce mitotic cellular division. In addition, MYC was found to induce Cyclin E; and Cyclin E in turn was found to be able to induce endo-reduplication. Hence, MYC appears induce inappropriate cell cycle transit, but not mitotic cellular division independent of p27 mediated inhibition of Cyclin E/Cdk2. Our results have implications for the mechanisms by which MYC overexpression dysregulates cell cycle transit, causes genomic destabilization and is restrained from causing tumorigenesis.
Deb-Basu
Debabrita
D
Division of Oncology, Departments of Medicine and Pathology, Stanford University, Stanford, California, USA.
Karlsson
Asa
A
Li
Qing
Q
Dang
Chi V
CV
Felsher
Dean W
DW
D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000235:genetics; D005786:Gene Expression Regulation; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats
D019927:Cyclin E; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA; D051357:Cyclin-Dependent Kinase 2