The identification of the essential role of cyclin-dependent kinases (CDKs) in the control of cell division has prompted the development of small-molecule CDK inhibitors as anticancer drugs. For many of these compounds, the precise mechanism of action in individual tumor types remains unclear as they simultaneously target different classes of CDKs - enzymes controlling the cell cycle progression as well as CDKs involved in the regulation of transcription. CDK inhibitors are also capable of activating p53 tumor suppressor in tumor cells retaining wild-type p53 gene by modulating MDM2 levels and activity. In the current study, we link, for the first time, CDK activity to the overexpression of the MDM4 (MDMX) oncogene in cancer cells. Small-molecule drugs targeting the CDK9 kinase, dinaciclib, flavopiridol, roscovitine, AT-7519, SNS-032, and DRB, diminished MDM4 levels and activated p53 in A375 melanoma and MCF7 breast carcinoma cells with only a limited effect on MDM2. These results suggest that MDM4, rather than MDM2, could be the primary transcriptional target of pharmacological CDK inhibitors in the p53 pathway. CDK9 inhibitor atuveciclib downregulated MDM4 and enhanced p53 activity induced by nutlin-3a, an inhibitor of p53-MDM2 interaction, and synergized with nutlin-3a in killing A375 melanoma cells. Furthermore, we found that human pluripotent stem cell lines express significant levels of MDM4, which are also maintained by CDK9 activity. In summary, we show that CDK9 activity is essential for the maintenance of high levels of MDM4 in human cells, and drugs targeting CDK9 might restore p53 tumor suppressor function in malignancies overexpressing MDM4.

• MeSH
• Cyclin-Dependent Kinase 9 antagonists & inhibitors   metabolism   MeSH
• Transcription, Genetic MeSH
• Imidazoles pharmacology   MeSH
• Protein Kinase Inhibitors pharmacology   MeSH
• Humans MeSH
• Melanoma genetics   metabolism   pathology   MeSH
• MCF-7 Cells MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Breast Neoplasms genetics   metabolism   pathology   MeSH
• Piperazines pharmacology   MeSH
• Pluripotent Stem Cells metabolism   MeSH
• Cell Cycle Proteins biosynthesis   genetics   metabolism   MeSH
• Proto-Oncogene Proteins c-mdm2 biosynthesis   genetics   metabolism   MeSH
• Proto-Oncogene Proteins biosynthesis   genetics   metabolism   MeSH
• Roscovitine pharmacology   MeSH
• Sulfonamides pharmacology   MeSH
• Drug Synergism MeSH
• Transfection MeSH
• Triazines pharmacology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• atuveciclib MeSH Browser
• CDK9 protein, human MeSH Browser
• Cdk9 protein, mouse MeSH Browser
• Cyclin-Dependent Kinase 9 MeSH
• Imidazoles MeSH
• Protein Kinase Inhibitors MeSH
• MDM2 protein, human MeSH Browser
• Mdm2 protein, mouse MeSH Browser
• MDM4 protein, human MeSH Browser
• Mdm4 protein, mouse MeSH Browser
• nutlin 3 MeSH Browser
• Piperazines MeSH
• Cell Cycle Proteins MeSH
• Proto-Oncogene Proteins c-mdm2 MeSH
• Proto-Oncogene Proteins MeSH
• Roscovitine MeSH
• Sulfonamides MeSH
• Triazines MeSH

Chronic inflammation with a wide spectrum of connected diseases (e [...].

• MeSH
• Phytochemicals pharmacology   therapeutic use   MeSH
• Humans MeSH
• Drug Discovery MeSH
• Gene Expression Regulation drug effects   MeSH
• Signal Transduction drug effects   MeSH
• Medicine, Chinese Traditional MeSH
• Inflammation drug therapy   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Introductory Journal Article MeSH
• Editorial MeSH
• Names of Substances
• Phytochemicals MeSH