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CDK9 activity is critical for maintaining MDM4 overexpression in tumor cells
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CDK9 activity is critical for maintaining MDM4 overexpression in tumor cells
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Journal Article
CDK9 activity is critical for maintaining MDM4 overexpression in tumor cells
2020
Overview
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.
Publisher
Nature Publishing Group UK,Springer Nature B.V
Subject
/ 13/109
/ 13/31
/ 13/89
/ 14/19
/ 38
/ 38/1
/ Animals
/ Biomedical and Life Sciences
/ Breast Neoplasms - metabolism
/ Breast Neoplasms - pathology
/ Cell Cycle Proteins - biosynthesis
/ Cell Cycle Proteins - genetics
/ Cell Cycle Proteins - metabolism
/ Cyclin-Dependent Kinase 9 - antagonists & inhibitors
/ Cyclin-Dependent Kinase 9 - metabolism
/ Humans
/ Kinases
/ Melanoma
/ Mice
/ Pluripotent Stem Cells - metabolism
/ Protein Kinase Inhibitors - pharmacology
/ Proto-Oncogene Proteins - biosynthesis
/ Proto-Oncogene Proteins - genetics
/ Proto-Oncogene Proteins - metabolism
/ Proto-Oncogene Proteins c-mdm2 - biosynthesis
/ Proto-Oncogene Proteins c-mdm2 - genetics
