CDK9 activity is critical for maintaining MDM4 overexpression
in tumor cells

J 2020

CDK9 activity is critical for maintaining MDM4 overexpression in tumor cells

ŠTĚTKOVÁ, Monika, Kateřina GROWKOVÁ, Petr FOJTÍK, Barbora VALČÍKOVÁ, Veronika PALUŠOVÁ et. al.

Basic information

Original name

CDK9 activity is critical for maintaining MDM4 overexpression in tumor cells

Authors

ŠTĚTKOVÁ, Monika (203 Czech Republic, belonging to the institution), Kateřina GROWKOVÁ (203 Czech Republic, belonging to the institution), Petr FOJTÍK (203 Czech Republic, belonging to the institution), Barbora VALČÍKOVÁ (203 Czech Republic, belonging to the institution), Veronika PALUŠOVÁ (703 Slovakia, belonging to the institution), Amandine VERLANDE (250 France, belonging to the institution), Radek JORDA (203 Czech Republic), Vladimír KRYŠTOF (203 Czech Republic), Václav HEJRET (203 Czech Republic, belonging to the institution), Panagiotis ALEXIOU (300 Greece, belonging to the institution), Vladimír ROTREKL (203 Czech Republic, belonging to the institution) and Stjepan ULDRIJAN (203 Czech Republic, guarantor, belonging to the institution)

Edition

CELL DEATH & DISEASE, LONDON, NATURE PUBLISHING GROUP, 2020, 2041-4889

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10601 Cell biology

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 8.469

RIV identification code

RIV/00216224:14110/20:00114362

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1038/s41419-020-02971-3

UT WoS

000573087600002

Keywords in English

CDK9; MDM4; tumor cells

Abstract

V originále

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.

Links

GA14-12166S, research and development project

Name: Regulace dráhy nádorového supresoru p53 novými vazebnými partnery onkogenů Mdm2 a Mdm4

Investor: Czech Science Foundation

MUNI/A/0951/2019, interní kód MU

Name: Buněčná a molekulární biologie pro Biomedicínské vědy

Investor: Masaryk University, Category A

MUNI/A/1087/2018, interní kód MU

Name: Molekulární a buněčná biologie pro biomedicínské vědy

Investor: Masaryk University, Category A

Citovat

ŠTĚTKOVÁ, Monika, Kateřina GROWKOVÁ, Petr FOJTÍK, Barbora VALČÍKOVÁ, Veronika PALUŠOVÁ, Amandine VERLANDE, Radek JORDA, Vladimír KRYŠTOF, Václav HEJRET, Panagiotis ALEXIOU, Vladimír ROTREKL and Stjepan ULDRIJAN. CDK9 activity is critical for maintaining MDM4 overexpression in tumor cells. CELL DEATH & DISEASE. LONDON: NATURE PUBLISHING GROUP, 2020, vol. 11, No 9, p. 1-14. ISSN 2041-4889. Available from: https://dx.doi.org/10.1038/s41419-020-02971-3.

@article{1685077,
   author = {Štětková, Monika and Growková, Kateřina and Fojtík, Petr and Valčíková, Barbora and Palušová, Veronika and Verlande, Amandine and Jorda, Radek and Kryštof, Vladimír and Hejret, Václav and Alexiou, Panagiotis and Rotrekl, Vladimír and Uldrijan, Stjepan},
   article_location = {LONDON},
   article_number = {9},
   doi = {http://dx.doi.org/10.1038/s41419-020-02971-3},
   keywords = {CDK9; MDM4; tumor cells},
   language = {eng},
   issn = {2041-4889},
   journal = {CELL DEATH & DISEASE},
   title = {CDK9 activity is critical for maintaining MDM4 overexpression in tumor cells},
   url = {https://www.nature.com/articles/s41419-020-02971-3.pdf},
   volume = {11},
   year = {2020}
}

TY  - JOUR
ID  - 1685077
AU  - Štětková, Monika - Growková, Kateřina - Fojtík, Petr - Valčíková, Barbora - Palušová, Veronika - Verlande, Amandine - Jorda, Radek - Kryštof, Vladimír - Hejret, Václav - Alexiou, Panagiotis - Rotrekl, Vladimír - Uldrijan, Stjepan
PY  - 2020
TI  - CDK9 activity is critical for maintaining MDM4 overexpression in tumor cells
JF  - CELL DEATH & DISEASE
VL  - 11
IS  - 9
SP  - 1-14
EP  - 1-14
PB  - NATURE PUBLISHING GROUP
SN  - 20414889
KW  - CDK9
KW  - MDM4
KW  - tumor cells
UR  - https://www.nature.com/articles/s41419-020-02971-3.pdf
L2  - https://www.nature.com/articles/s41419-020-02971-3.pdf
N2  - 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.
ER  -

ŠTĚTKOVÁ, Monika, Kateřina GROWKOVÁ, Petr FOJTÍK, Barbora VALČÍKOVÁ, Veronika PALUŠOVÁ, Amandine VERLANDE, Radek JORDA, Vladimír KRYŠTOF, Václav HEJRET, Panagiotis ALEXIOU, Vladimír ROTREKL and Stjepan ULDRIJAN. CDK9 activity is critical for maintaining MDM4 overexpression in tumor cells. \textit{CELL DEATH \&{} DISEASE}. LONDON: NATURE PUBLISHING GROUP, 2020, vol.~11, No~9, p.~1-14. ISSN~2041-4889. Available from: https://dx.doi.org/10.1038/s41419-020-02971-3.

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