CDK9 activity is critical for maintaining MDM4 overexpression in tumor cells
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61389030%3A_____%2F20%3A00533489" target="_blank" >RIV/61389030:_____/20:00533489 - isvavai.cz</a>
Alternative codes found
RIV/00216224:14110/20:00114362 RIV/00159816:_____/20:00073535 RIV/61989592:15310/20:73604866
Result on the web
<a href="http://doi.org/10.1038/s41419-020-02971-3" target="_blank" >http://doi.org/10.1038/s41419-020-02971-3</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1038/s41419-020-02971-3" target="_blank" >10.1038/s41419-020-02971-3</a>
Alternative languages
Result language
angličtina
Original language name
CDK9 activity is critical for maintaining MDM4 overexpression in tumor cells
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10603 - Genetics and heredity (medical genetics to be 3)
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2020
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Cell Death & Disease
ISSN
2041-4889
e-ISSN
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Volume of the periodical
11
Issue of the periodical within the volume
9
Country of publishing house
GB - UNITED KINGDOM
Number of pages
14
Pages from-to
754
UT code for WoS article
000573087600002
EID of the result in the Scopus database
2-s2.0-85091053112