Figure 4 - available via license: Creative Commons Attribution 4.0 International
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An overview of CDK functions in the cell. Each CDK (in orange boxes) is shown in a complex with its major partner (green) - for clarity, only a few substrates are depicted. Most CDKs function in the nucleus (orange background), whereas a few family members are attached to the cell membrane or display cytoplasmic activities (blue background). Classical cell cycle CDKs - Cdk4, Cdk6, Cdk2 and Cdk1 - regulate the transitions through the different phases of the cell-division cycle. These activities are at least partially mediated by the control of multiple transcription factors (TFs) or regulatory elements such as the retinoblastoma protein (Rb). Cdk10 and Cdk11 also control transcription by phosphorylating TFs, hormone receptors and associated regulators (HRs), or splicing factors (SPFs). Cdk7, Cdk9 and Cdk12 directly phosphorylate the C-terminal domain (CTD) of RNA polymerase II (RNAPII), thus modulating the different phases of generation of transcripts. The Mediator complex is specifically regulated by Cdk8 or the highly related Cdk19. Cdk7 functions as a CDK-activating kinase (CAK) by directly phosphorylating several of the CDKs mentioned above. Cdk5 displays many functions in the cell, but it is better known for its function in the control of neuron-specific proteins such as Tau. The members of the Cdk14 subfamily, such as Cdk14 itself or Cdk16, are activated at the membrane by cyclin Y and also participate in many different pathways, such as Wnt-dependent signaling or signal transduction in the primary cilium. It is important to note that, for clarity, many interactions between CDKs and other partners, substrates or cellular processes are not shown - for instance, Cdk1 can bind to other cyclins and can also phosphorylate more than 100 substrates during mitotic entry that are not indicated here. CAK, CDK-activating kinase; CDK, cyclin-dependent kinase; CTD, C-terminal domain; Rb, retinoblastoma protein; RNAPII, RNA polymerase II; SPF, splicing factor; TF, transcription factor.
Source publication
Cyclin-dependent kinases (CDKs) are protein kinases characterized by needing a separate subunit - a cyclin - that provides domains essential for enzymatic activity. CDKs play important roles in the control of cell division and modulate transcription in response to several extra- and intracellular cues. The evolutionary expansion of the CDK family i...
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Background
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Citations
... CDKs are activated when they interact with cyclins. Therefore, CDKs are potential targets for tumor treatment [1][2][3]. ...
The regulation of the cancer cell cycle heavily relies on cyclin-dependent kinases (CDKs). Targeting CDKs has been identified as a promising approach for effective cancer therapy. In recent years, there has been significant attention paid towards developing small-molecule CDK inhibitors in the field of drug discovery. Notably, five such inhibitors have already received regulatory approval for the treatment of different cancers, including breast tumors, lung malignancies, and hematological malignancies. This review provides an overview of the synthetic routes used to produce 17 representative small-molecule CDK inhibitors that have obtained regulatory approval or are currently being evaluated through clinical trials. It also discusses their clinical applications for treating CDK-related diseases and explores the challenges and limitations associated with their use in a clinical setting, which will stimulate the further development of novel CDK inhibitors. By integrating therapeutic applications, synthetic methodologies, and mechanisms of action observed in various clinical trials involving these CDK inhibitors, this review facilitates a comprehensive understanding of the versatile roles and therapeutic potential offered by interventions targeting CDKs.
... Zhou, et al., 2021). CDK1 is an essential regulator of cell cycle progression and regulation (Malumbres, 2014). GO-term analysis further shows it is involved in signal transduction, negative regulation of apoptosis, and mitotic cell cycle phase transition. ...
Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor associated with high fatality rates, poor prognosis, and limited treatment options. To enhance our understanding of the disease and pave the way for targeted therapies, it is imperative to identify key genes influencing GBM progression. In this study, we harnessed RNA-Seq gene count data from GBM patients sourced from the GEO database, conducting an in-depth analysis of gene expression patterns. Our investigation involved the stratification of samples into two distinct sets, Group I and Group II, comparing low-grade and GBM tumor samples, respectively. Subsequently, we performed differential expression analysis and enrichment analysis to uncover significant gene signatures. To elucidate the protein-protein interactions that underlie GBM, we leveraged the STRING plugin within Cytoscape for comprehensive network visualization and analysis. By applying Maximal clique centrality (MCC) scores, we identified a set of 10 hub genes in each group. These hub genes were subjected to survival analysis, highlighting their prognostic relevance. In Group I, comprising BUB1, DLGAP5, BUB1B, CDK1, TOP2A, CDC20, KIF20A, ASPM, BIRC5, and CCNB2, these genes emerged as potential biomarkers associated with the transition to low-grade tumors. In Group II, encompassing LIF, LBP, CSF3, IL6, CCL2, SAA1, CCL20, MMP9, CXCL10, and MMP1, these genes were implicated in transforming adult glioblastoma. Kaplan–Meier's overall survival analysis of these hub genes revealed that modifications, particularly upregulation of these candidate genes, were associated with reduced survival in GBM patients. The findings underscore the significance of genomic alterations and differential gene expression in GBM, presenting opportunities for early diagnosis and targeted therapeutic interventions. This study offers valuable insights into the potential avenues for improving the clinical management of GBM.
... Recent insights have shown that this change is caused by mutations in proteins that inhibit apoptosis and that participate in pathways that regulate cell cycle progression rather than mechanisms that promote uncontrolled cell cycle progression [25]. The cell cycle is regulated by various signalling pathways, including pathways that involve cell cycle proteins and cyclin-dependent kinases (CDKs) [26], pathways that transcriptionally regulate G1-S progression [27,28], checkpoint signalling pathways [29] and pathways that regulate ubiquitin ligases [30]. Notably, the p53 gene is a well-known tumour suppressor that is crucial in inducing apoptosis and cell cycle arrest [31,32]. ...
Lung adenocarcinoma (LUAD) is the most widespread cancer in the world, and its development is associated with complex biological mechanisms that are poorly understood. Here, we revealed a marked upregulation in the mRNA level of C1orf131 in LUAD samples compared to non-tumor tissue samples in The Cancer Genome Atlas (TCGA). Depletion of C1orf131 suppressed cell proliferation and growth, whereas it stimulated apoptosis in LUAD cells. Mechanistic investigations revealed that C1orf131 knockdown induced cell cycle dysregulation via the AKT and p53/p21 signalling pathways. Additionally, C1orf131 knockdown blocked cell migration through the modulation of epithelial–mesenchymal transition (EMT) in lung adenocarcinoma. Notably, we identified the C1orf131 protein nucleolar localization sequence, which included amino acid residues 137–142 (KKRKLT) and 240–245 (KKKRKG). Collectively, C1orf131 has potential as a novel therapeutic marker for patients in the future, as it plays a vital role in the progression of lung adenocarcinoma.
... Cell cycle, an ordered, irreversible process, is choreographed by cyclin-dependent kinases (CDKs) together with their cyclin chaperones [16]. One of the important mechanisms how glycolysis promotes tumor development is the acceleration of cell cycle process. ...
Metabolic reprogramming has been demonstrated to have a significant impact on the biological behaviors of tumor cells, among which glycolysis is an important form. Recent research has revealed that the heightened glycolysis levels, the abnormal expression of glycolytic enzymes, and the accumulation of glycolytic products could regulate the growth, proliferation, invasion, and metastasis of tumor cells and provide a favorable microenvironment for tumor development and progression. Based on the distinctive glycolytic characteristics of tumor cells, novel imaging tests have been developed to evaluate tumor proliferation and metastasis. In addition, glycolytic enzymes have been found to serve as promising biomarkers in tumor, which could provide assistance in the early diagnosis and prognostic assessment of tumor patients. Numerous glycolytic enzymes have been identified as potential therapeutic targets for tumor treatment, and various small molecule inhibitors targeting glycolytic enzymes have been developed to inhibit tumor development and some of them are already applied in the clinic. In this review, we systematically summarized recent advances of the regulatory roles of glycolysis in tumor progression and highlighted the potential clinical significance of glycolytic enzymes and products as novel biomarkers and therapeutic targets in tumor treatment.
... Inhibiting Cdk2 results in an accumulation of centrioles at Stage 1 of centriole engagement, implying that its activity is required for the transition from Stage 1 to Stage 2. CDK2 is activated by forming complexes with either cyclin E or cyclin A (Fig. 2e, 3a) 27 . To elucidate the specific cyclin contributing to the configuration and mechanism changes behind the transition from Stage 1 to Stage 2, we knocked down each cyclin and observed centrioles during S phase. ...
... It is made In late S phase, the configuration and the mechanism of centriole engagement changes: daughter centrioles bloom and the cartwheel becomes dispensable for maintaining the engagement (Fig. 2j, Stage 2→3). In this phase, cyclin A, which forms a complex with CDK2 27 , begins to accumulate (Fig. 3a). We therefore examined whether the CDK2-cyclin A complex causes the transition from Stage 2 to Stage 3. In Cep57L1 knockout cells, Cep57 depletion led to precocious centriole disengagement in late S phase, whereas simultaneous depletion of cyclin A reduced this phenotype (Fig. 3b, c, siCep57: 55.0 ± 4.2%, siCep57+siCCNA2: 21.1% ± 7.1%). ...
The DNA and the centrioles are the only cellular structures that uniquely replicate to produce identical copies, which is crucial for proper chromosome segregation in mitosis. A new centriole termed "daughter" is progressively assembled adjacent to a pre-existing, "mother" centriole. Only after the daughter centriole is structurally completed as an identical copy, it disengages from its mother to become the core of a new functional centrosome. The mechanisms preventing precocious disengagement of the immature copy have been previously unknown. Here, we identify three key centriole-associated mechanisms that maintain the mother-daughter engagement: the cartwheel, the torus, and the pericentriolar material pathways. Among these, the torus is critical for establishing the characteristic orthogonal engagement between the mother and daughter centrioles. Furthermore, we show that the engagement mediated by the cartwheel and the torus pathways is released stepwise through structural changes in the daughter centriole, known as centriole blooming and centriole distancing, respectively. Disruption at any stage of these structural transitions leads to the failure of all subsequent steps, ultimately blocking centriole disengagement and centrosome conversion at the end of mitosis. Overall, this study provides a comprehensive understanding of how the maturing daughter centriole progressively disengages from its mother through multiple maturation steps, to ensure its complete structure and conversion into an independent centrosome.
... Cyclin-dependent kinases (CDKs) are a family of protein kinases that have been shown to be important regulators of cell cycle progression [119]. The activity of CDKs is controlled by their association with cyclins and by the action of CDK inhibitors (CDKIs). ...
Michael acceptors represent a class of compounds with potential anti-cancer properties. They act by binding to nucleophilic sites in biological molecules, thereby disrupting cancer cell function and inducing cell death. This mode of action, as well as their ability to be modified and targeted, makes them a promising avenue for advancing cancer therapy. We are investigating the molecular mechanisms underlying Michael acceptors and their interactions with cancer cells, in particular their ability to interfere with cellular processes and induce apoptosis. The anti-cancer properties of Michael acceptors are not accidental but are due to their chemical structure and reactivity. The electrophilic nature of these compounds allows them to selectively target nucleophilic residues on disease-associated proteins, resulting in significant therapeutic benefits and minimal toxicity in various diseases. This opens up new perspectives for the development of more effective and precise cancer drugs. Nevertheless, further studies are essential to fully understand the impact of our discoveries and translate them into clinical practice.
... Cyclin-dependent kinases (CDKs) are a class of protein kinases that play a key role in the regulation of the cell cycle [1][2][3][4][5][6][7][8][9][10]. According to their respective functions, CDKs can be categorized into two major groups: cell cycle-regulated CDKs (such as CDK1, CDK2, CDK4, and CDK6) and transcription-regulated CDKs (such as CDK7, CDK8, and CDK9) [11,12]. ...
CDK6 plays a key role in the regulation of the cell cycle and is considered a crucial target for cancer therapy. In this work, conformational transitions of CDK6 were identified by using Gauss-ian accelerated molecular dynamics (GaMD), deep learning (DL), and free energy landscapes (FELs). DL finds that the binding pocket as well as the T-loop binding to the Vcyclin protein are involved in obvious differences of conformation contacts. This result suggests that the binding pocket of inhibitors (LQQ and AP9) and the binding interface of CDK6 to the Vcyclin protein play a key role in the function of CDK6. The analyses of FELs reveal that the binding pocket and the T-loop of CDK6 have disordered states. The results from principal component analysis (PCA) indicate that the binding of the Vcyclin protein affects the fluctuation behavior of the T-loop in CDK6. Our QM/MM-GBSA calculations suggest that the binding ability of LQQ to CDK6 is stronger than AP9 with or without the binding of the Vcyclin protein. Interaction networks of inhibitors with CDK6 were analyzed and the results reveal that LQQ contributes more hydrogen binding interactions (HBIs) and hot interaction spots with CDK6. In addition, the binding pocket endures flexibility changes from opening to closing states and the Vcyclin protein plays an important role in the stabilizing conformation of the T-loop. We anticipate that this work could provide useful information for further understanding the function of CDK6 and developing new promising inhibitors targeting CDK6.
... Also, PLK1 plays a critical role in LUAD progression by regulating necroptosis and immune infiltration, and may serve as a potential therapeutic target for immunotherapy [57,58]. Cyclin dependent kinases (CDKs) are serine/threonine kinases that are proposed as promising candidate targets for cancer treatment [59]. Deregulation of CDK1 has been shown to be closely associated with tumorigenesis. ...
Background
6-Methoxydihydrosanguinarine (6-MDS) has shown promising potential in fighting against a variety of malignancies. Yet, its anti‑lung adenocarcinoma (LUAD) effect and the underlying mechanism remain largely unexplored. This study sought to explore the targets and the probable mechanism of 6-MDS in LUAD through network pharmacology and experimental validation.
Methods
The proliferative activity of human LUAD cell line A549 was evaluated by Cell Counting Kit-8 (CCK8) assay. LUAD related targets, potential targets of 6-MDS were obtained from databases. Venn plot analysis were performed on 6-MDS target genes and LUAD related genes to obtain potential target genes for 6-MDS treatment of LUAD. The Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database was utilized to perform a protein-protein interaction (PPI) analysis, which was then visualized by Cytoscape. The hub genes in the network were singled out by CytoHubba. Metascape was employed for GO and KEGG enrichment analyses. molecular docking was carried out using AutoDock Vina 4.2 software. Gene expression levels, overall survival of hub genes were validated by the GEPIA database. Protein expression levels, promotor methylation levels of hub genes were confirmed by the UALCAN database. Timer database was used for evaluating the association between the expression of hub genes and the abundance of infiltrating immune cells. Furthermore, correlation analysis of hub genes expression with immune subtypes of LUAD were performed by using the TISIDB database. Finally, the results of network pharmacology analysis were validated by qPCR.
Results
Experiments in vitro revealed that 6-MDS significantly reduced tumor growth. A total of 33 potential targets of 6-MDS in LUAD were obtained by crossing the LUAD related targets with 6-MDS targets. Utilizing CytoHubba, a network analysis tool, the top 10 genes with the highest centrality measures were pinpointed, including MMP9, CDK1, TYMS, CCNA2, ERBB2, CHEK1, KIF11, AURKB, PLK1 and TTK. Analysis of KEGG enrichment hinted that these 10 hub genes were located in the cell cycle signaling pathway, suggesting that 6-MDS may mainly inhibit the occurrence of LUAD by affecting the cell cycle. Molecular docking analysis revealed that the binding energies between 6-MDS and the hub proteins were all higher than − 6 kcal/Mol with the exception of AURKB, indicating that the 9 targets had strong binding ability with 6-MDS.These results were corroborated through assessments of mRNA expression levels, protein expression levels, overall survival analysis, promotor methylation level, immune subtypes andimmune infiltration. Furthermore, qPCR results indicated that 6-MDS can significantly decreased the mRNA levels of CDK1, CHEK1, KIF11, PLK1 and TTK.
Conclusions
According to our findings, it appears that 6-MDS could possibly serve as a promising option for the treatment of LUAD. Further investigations in live animal models are necessary to confirm its potential in fighting cancer and to delve into the mechanisms at play.
... CDK1 to CDK6 are involved in cell cycle regulation, while CDK7, CDK8, CDK9, CDK11, and CDK20 are primarily involved in transcriptional regulation. More particularly, CDK7, CDK8, and CDK9 control the activity of RNA polymerase II in humans through the phosphorylation of its C-terminus domain, which catalyzes the synthesis of all mRNA precursors [1]. The inhibition of CDK activity by small molecules for the treatment of cancer has been extensively studied [2]. ...
Dysregulation of cyclin-dependent kinase 8 (CDK8) activity has been associated with many diseases, including colorectal and breast cancer. As usual in the CDK family, the activity of CDK8 is controlled by a regulatory protein called cyclin C (CycC). But, while human CDK family members are generally activated in two steps, that is, the binding of the cyclin to CDK and the phosphorylation of a residue in the CDK activation loop, CDK8 does not require the phosphorylation step to be active. Another peculiarity of CDK8 is its ability to be associated with CycC while adopting an inactive form. These specificities raise the question of the role of CycC in the complex CDK8–CycC, which appears to be more complex than the other members of the CDK family. Through molecular dynamics (MD) simulations and binding free energy calculations, we investigated the effect of CycC on the structure and dynamics of CDK8. In a second step, we particularly focused our investigation on the structural and molecular basis of the protein–protein interaction between the two partners by finely analyzing the energetic contribution of residues and simulating the transition between the active and the inactive form. We found that CycC has a stabilizing effect on CDK8, and we identified specific interaction hotspots within its interaction surface compared to other human CDK/Cyc pairs. Targeting these specific interaction hotspots could be a promising approach in terms of specificity to effectively disrupt the interaction between CDK8. The simulation of the conformational transition from the inactive to the active form of CDK8 suggests that the residue Glu99 of CycC is involved in the orientation of three conserved arginines of CDK8. Thus, this residue may assume the role of the missing phosphorylation step in the activation mechanism of CDK8. In a more general view, these results point to the importance of keeping the CycC in computational studies when studying the human CDK8 protein in both the active and the inactive form.
... Tightly regulated cell cycle progression is essential for maintaining cellular homeostasis. The four distinct stages (G1, S, G2, and M) are governed by the coordinated activity of 2 of 18 cyclin-dependent kinases (CDKs) and cyclin proteins [6][7][8][9]. Cell cycle-specific transcriptional control and protein degradation mechanisms further ensure the precise temporal regulation of these proteins [10]. During the G1 phase, in response to mitotic signals, D-type cyclins (D1, D2, and D3) bind and activate CDK4/6, leading to retinoblastoma protein (RB) phosphorylation [11,12]. ...
Lung adenocarcinoma (LUAD) is the most prevalent and aggressive subtype of lung cancer, exhibiting a dismal prognosis with a five-year survival rate below 5%. DEAD-box RNA helicase 18 (DDX18, gene symbol DDX18), a crucial regulator of RNA metabolism, has been implicated in various cellular processes, including cell cycle control and tumorigenesis. However, its role in LUAD pathogenesis remains elusive. This study demonstrates the significant upregulation of DDX18 in LUAD tissues and its association with poor patient survival (from public databases). Functional in vivo and in vitro assays revealed that DDX18 knockdown potently suppresses LUAD progression. RNA sequencing and chromatin immunoprecipitation experiments identified cyclin-dependent kinase 4 (CDK4), a cell cycle regulator, as a direct transcriptional target of DDX18. Notably, DDX18 depletion induced G1 cell cycle arrest, while its overexpression promoted cell cycle progression even in normal lung cells. Interestingly, while the oncogenic protein c-Myc bound to the DDX18 promoter, it did not influence its expression. Collectively, these findings establish DDX18 as a potential oncogene in LUAD, functioning through the CDK4-mediated cell cycle pathway. DDX18 may represent a promising therapeutic target for LUAD intervention.
