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.

Základní údaje

Originální název

CDK9 activity is critical for maintaining MDM4 overexpression in tumor cells

Autoři

ŠTĚTKOVÁ, Monika (203 Česká republika, domácí), Kateřina GROWKOVÁ (203 Česká republika, domácí), Petr FOJTÍK (203 Česká republika, domácí), Barbora VALČÍKOVÁ (203 Česká republika, domácí), Veronika PALUŠOVÁ (703 Slovensko, domácí), Amandine VERLANDE (250 Francie, domácí), Radek JORDA (203 Česká republika), Vladimír KRYŠTOF (203 Česká republika), Václav HEJRET (203 Česká republika, domácí), Panagiotis ALEXIOU (300 Řecko, domácí), Vladimír ROTREKL (203 Česká republika, domácí) a Stjepan ULDRIJAN (203 Česká republika, garant, domácí)

Vydání

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

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10601 Cell biology

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 8.469

Kód RIV

RIV/00216224:14110/20:00114362

Organizační jednotka

Lékařská fakulta

DOI

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

UT WoS

000573087600002

Klíčová slova anglicky

CDK9; MDM4; tumor cells

Štítky

14110513, CF BIOIT, podil, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 4. 3. 2021 12:31, Mgr. Tereza Miškechová

Anotace

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.

Návaznosti

GA14-12166S, projekt VaV

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

Investor: Grantová agentura ČR, Regulace dráhy nádorového supresoru p53 novými vazebnými partnery onkogenů Mdm2 a Mdm4

MUNI/A/0951/2019, interní kód MU

Název: Buněčná a molekulární biologie pro Biomedicínské vědy

Investor: Masarykova univerzita, Buněčná a molekulární biologie pro Biomedicínské vědy, DO R. 2020_Kategorie A - Specifický výzkum - Studentské výzkumné projekty

MUNI/A/1087/2018, interní kód MU

Název: Molekulární a buněčná biologie pro biomedicínské vědy

Investor: Masarykova univerzita, Molekulární a buněčná biologie pro biomedicínské vědy, DO R. 2020_Kategorie A - Specifický výzkum - Studentské výzkumné projekty

Citovat

ŠTĚTKOVÁ, Monika, Kateřina GROWKOVÁ, Petr FOJTÍK, Barbora VALČÍKOVÁ, Veronika PALUŠOVÁ, Amandine VERLANDE, Radek JORDA, Vladimír KRYŠTOF, Václav HEJRET, Panagiotis ALEXIOU, Vladimír ROTREKL a Stjepan ULDRIJAN. CDK9 activity is critical for maintaining MDM4 overexpression in tumor cells. CELL DEATH & DISEASE. LONDON: NATURE PUBLISHING GROUP, 2020, roč. 11, č. 9, s. 1-14. ISSN 2041-4889. Dostupné z: 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 a Stjepan ULDRIJAN. CDK9 activity is critical for maintaining MDM4 overexpression in tumor cells. \textit{CELL DEATH \&{} DISEASE}. LONDON: NATURE PUBLISHING GROUP, 2020, roč.~11, č.~9, s.~1-14. ISSN~2041-4889. Dostupné z: https://dx.doi.org/10.1038/s41419-020-02971-3.

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