CDK2 Transcriptional Repression Is an Essential Effector in p53-Dependent Cellular Senescence—Implications for Therapeutic Intervention

Zalzali, Hasan; Nasr, Bilal; Harajly, Mohamad; Basma, Hussein; Ghamloush, Farah; Ghayad, Sandra E.; Ghanem, Noël; Evan, Gérard I.; Saab, Raya

doi:10.1158/1541-7786.mcr-14-0163

Cited by 25 publications

(24 citation statements)

References 39 publications

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“…While CDK2 necessity in G1/S checkpoint control and its possible compensation for by analogs such as CDK1 were discussed [39][40][41], more recent results suggest that CDK2 is actually required for properly timed cell-cycle progression [42], which implies that a downregulation of this protein would theoretically lead to an increased number of cells in the G1 phase. Additionally, CDK2 was also proposed as an actor in G2 cell-cycle arrest after exposure to 2 µM OTA due to its role in cell senescence [43,44]. However, we observed that the G2 cell-cycle arrest induced by high concentrations of OTA was not influenced after CDK2 overexpression, which goes against the idea of CDK2 being a regulator of this process.…”

Section: Discussioncontrasting

confidence: 69%

Weighted Correlation Network Analysis Reveals CDK2 as a Regulator of a Ubiquitous Environmental Toxin-Induced Cell-Cycle Arrest

Dubourg

Nolze

Kopf

et al. 2020

Cells

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Environmental food contaminants constitute a threat to human health. For instance, the globally spread mycotoxin Ochratoxin A (OTA) contributes to chronic kidney damage by affecting proximal tubule cells via unknown mechanisms. We applied a top-down approach to identify relevant toxicological mechanisms of OTA using RNA-sequencing followed by in-depth bioinformatics analysis and experimental validation. Differential expression analyses revealed that OTA led to the regulation of gene expression in kidney human cell lines, including for genes enriched in cell cycle-related pathways, and OTA-induced gap 1 and 2 (G1 and G2) cell-cycle arrests were observed. Weighted correlation network analysis highlighted cyclin dependent kinase 2 (CDK2) as a putative key regulator of this effect. CDK2 was downregulated by OTA exposure, and its overexpression partially blocked the OTA-induced G1 but not G2 cell-cycle arrest. We, therefore, propose CDK2 as one of the key regulators of the G1 cell-cycle arrest induced by low nanomolar concentrations of OTA.

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Section: Discussioncontrasting

confidence: 69%

Weighted Correlation Network Analysis Reveals CDK2 as a Regulator of a Ubiquitous Environmental Toxin-Induced Cell-Cycle Arrest

Dubourg

Nolze

Kopf

et al. 2020

Cells

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“…CDK2 is a vital regulator of S-phase progression and has been regarded as an anticancer drug target in several studies [ 30 , 31 ]. Recent studies show that for both DNA damage- and oncogene-induced cellular senescence, CDK2 transcript and protein are inhibited in a p53- and RB-dependent manner, and this repression is necessary for cell cycle exit during senescence, suggesting that there may exist a potential relationship between TP53 and CDK2 [ 32 ]. Limited by few studies about the relationship between TP53 and CDK2 in glioma, further research is necessary to clarify the underlying correlation and mechanism between TP53 and CDK2.…”

Section: Discussionmentioning

confidence: 99%

Identification of Core Biomarkers Associated with Outcome in Glioma: Evidence from Bioinformatics Analysis

Geng

et al. 2018

Disease Markers

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Glioma is the most common neoplasm of the central nervous system (CNS); the progression and outcomes of which are affected by a complicated network of genes and pathways. We chose a gene expression profile of GSE66354 from GEO database to search core biomarkers during the occurrence and development of glioma. A total of 149 samples, involving 136 glioma and 13 normal brain tissues, were enrolled in this article. 1980 differentially expressed genes (DEGs) including 697 upregulated genes and 1283 downregulated genes between glioma patients and healthy individuals were selected using GeoDiver and GEO2R tool. Then, gene ontology (GO) analysis as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were carried out using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Moreover, Cytoscape with Search Tool for the Retrieval of Interacting Genes (STRING) and Molecular Complex Detection (MCODE) plug-in was employed to imagine protein-protein interaction (PPI) of these DEGs. The upregulated genes were enriched in cell cycle, ECM-receptor interaction, and p53 signaling pathway, while the downregulated genes were enriched in retrograde endocannabinoid signaling, glutamatergic synapse, morphine addiction, GABAergic synapse, and calcium signaling pathway. Subsequently, 4 typical modules were discovered by the PPI network utilizing MCODE software. Besides, 15 hub genes were chosen according to the degree of connectivity, including TP53, CDK1, CCNB1, and CCNB2, the Kaplan-Meier analysis of which was further identified. In conclusion, this bioinformatics analysis indicated that DEGs and core genes, such as TP53, might influence the development of glioma, especially in tumor proliferation, which were expected to be promising biomarkers for diagnosis and treatment of glioma.

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“…Therefore, attention is increasingly being focused on cell cycle, as a potential target for therapeutic intervention [35, 57, 58]. In this context, our finding that aspirin and salicylic acid down-regulate cyclin A2 /CDK2 protein and mRNAs in multiple cancer cell lines should initiate new thinking and research on these age-old drugs in cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

Cyclin A2 and CDK2 as Novel Targets of Aspirin and Salicylic Acid: A Potential Role in Cancer Prevention

Dachineni

Kumar

et al. 2016

Molecular Cancer Research

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Data emerging from the past 10 years have consolidated the rationale for investigating the use of aspirin as a chemopreventive agent; however, the mechanisms leading to its anti-cancer effects are still being elucidated. We hypothesized that aspirin’s chemopreventive actions may involve cell cycle regulation through modulation of the levels or activity of cyclin A2/cyclin dependent kinase-2 (CDK2). In this study, HT-29 and other diverse panel of cancer cells were used to demonstrate that both aspirin and its primary metabolite, salicylic acid, decreased cyclin A2 (CCNA2) and CDK2 protein and mRNA levels. The down regulatory effect of either drugs on cyclin A2 levels was prevented by pretreatment with lactacystin, an inhibitor of proteasomes, suggesting the involvement of 26S proteasomes. In-vitro kinase assays showed that lysates from cells treated with salicylic acid had lower levels of CDK2 activity. Importantly, three independent experiments revealed that salicylic acid directly binds to CDK2. Firstly, inclusion of salicylic acid in naïve cell lysates, or in recombinant CDK2 preparations, increased the ability of the anti-CDK2 antibody to immunoprecipitate CDK2, suggesting that salicylic acid may directly bind and alter its conformation. Secondly, in 8-anilino-1-naphthalene-sulfonate (ANS)-CDK2 fluorescence assays, pre-incubation of CDK2 with salicylic acid, dose-dependently quenched the fluorescence due to ANS. Thirdly, computational analysis using molecular docking studies identified Asp145 and Lys33 as the potential sites of salicylic acid interactions with CDK2. These results demonstrate that aspirin and salicylic acid down-regulate cyclin A2/CDK2 proteins in multiple cancer cell lines, suggesting a novel target and mechanism of action in chemoprevention. Implications Biochemical and structural studies indicate that the anti-proliferative actions of aspirin are mediated through cyclin A2/CDK2.

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CDK2 Transcriptional Repression Is an Essential Effector in p53-Dependent Cellular Senescence—Implications for Therapeutic Intervention

Cited by 25 publications

References 39 publications

Weighted Correlation Network Analysis Reveals CDK2 as a Regulator of a Ubiquitous Environmental Toxin-Induced Cell-Cycle Arrest

Weighted Correlation Network Analysis Reveals CDK2 as a Regulator of a Ubiquitous Environmental Toxin-Induced Cell-Cycle Arrest

Identification of Core Biomarkers Associated with Outcome in Glioma: Evidence from Bioinformatics Analysis

Cyclin A2 and CDK2 as Novel Targets of Aspirin and Salicylic Acid: A Potential Role in Cancer Prevention

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