ArticleCell death & disease2020
CDK9 activity is critical for maintaining MDM4 overexpression in tumor cells.
Article in Cell death & disease, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
19 citing papers in PubMed.
- The Role of Transcriptional and Atypical Cyclin-Dependent Protein Kinases in Melanoma.Cancers · 2026Review
- Targeting Transcriptional Cyclin-Dependent Kinases in Cancer.Molecular cancer therapeutics · 2025Review
- Harnessing p53 for targeted cancer therapy: new advances and future directions.Transcription · 2025Review
- Targeting CDK9 with selective inhibitors or degraders in tumor therapy: an overview of recent developments.Cancer biology & therapy · 2023Review
- Inhibition of CDK12 elevates cancer cell dependence on P-TEFb by stimulation of RNA polymerase II pause release.Nucleic acids research · 2023Article
- The prognostic role of p53 and its correlation with CDK9 in urothelial carcinoma.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2023Article
- Dynamic regulation of P-TEFb by 7SK snRNP is integral to the DNA damage response to regulate chemotherapy sensitivity.iScience · 2022Article
- Review
- Exploration and validation of metastasis-associated genes for skin cutaneous melanoma.Scientific reports · 2022Article
- Targeting cyclin-dependent kinase 9 in cancer therapy.Acta pharmacologica Sinica · 2022Review
- CDK9 inhibitors in cancer research.RSC medicinal chemistry · 2022Review
- The Prognostic Role of CDK9 in Bladder Cancer.Cancers · 2022Article
- CDK9 is up-regulated and associated with prognosis in patients with papillary thyroid carcinoma.Medicine · 2022Observational
- CDK9 inhibitors in multiple myeloma: a review of progress and perspectives.Medical oncology (Northwood, London, England) · 2022Review
- Article
- Genome-wide identification of cyclin-dependent kinase (CDK) genes affecting adipocyte differentiation in cattle.BMC genomics · 2021Article
- VEGFC/FLT4-induced cell-cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cells.Cell reports · 2021Article
- A Gene Expression Signature to Predict Nucleotide Excision Repair Defects and Novel Therapeutic Approaches.International journal of molecular sciences · 2021Article
- The involvement of cyclin-dependent kinase 7 (CDK7) and 9 (CDK9) in coordinating transcription and cell cycle checkpoint regulation.Cell cycle (Georgetown, Tex.)Review
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Authors and funding
12 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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