MDM2 controls the timely expression of cyclin A to regulate the cell cycle.
Overexpression of MDM2 has been related to oncogenesis. In this communication, we present evidence to show that MDM2 controls the cell cycle-dependent expression of cyclin A by using a pathway that ensures its timely expression. MDM2 does not inhibit cyclin D or E expression. Silencing of endogenous MDM2 expression elevates cyclin A expression. The p53-binding domain of MDM2 harbors a SWIB region homologous to a conserved domain of a chromosome remodeling factor BRG1-associated protein. The SWIB domain of MDM2 inhibits cyclin A expression in a p53- and BRG1-dependent fashion, suggesting that MDM2 interferes with p53 binding of the BRG1 complex freeing it to repress cyclin A expression. Silencing of cyclin-dependent kinase (cdk) inhibitor p16 prevents MDM2-mediated inhibition of cyclin A expression, implicating its role in the process. MDM2-mediated repression of cyclin A expression induces G(1)-S arrest, which can be rescued by ectopic expression of cyclin A. Cancer cells lacking p53, p16, or BRG1 escape MDM2-mediated repression of cyclin A expression and growth arrest. Our data propose a novel mechanism by which MDM2 controls the cell cycle in normal cells and how cancer cells may escape this important safety barrier.
Frum
Rebecca
R
Department of Biochemistry and Molecular Biology, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
Ramamoorthy
Mahesh
M
Mohanraj
Lathika
L
Deb
Sumitra
S
Deb
Swati Palit
SP
D002453:Cell Cycle; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D019925:Cyclin A / Q000378:metabolism*; D019927:Cyclin E / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004265:DNA Helicases / Q000378:metabolism; D015536:Down-Regulation; D005434:Flow Cytometry; D016193:G1 Phase; D006801:Humans; D018613:Microscopy, Confocal; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D019925:Cyclin A; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C084108:SMARCA4 protein, human; D004265:DNA Helicases