14 results
Search Results
2. Beyond cell cycle regulation: The pleiotropic function of CDK4 in cancer.
- Author
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Ziegler DV, Parashar K, and Fajas L
- Subjects
- Humans, Cyclin-Dependent Kinase 4 genetics, Cyclin-Dependent Kinase 4 metabolism, Cyclin D metabolism, Phosphorylation, Cell Cycle genetics, Cell Cycle Proteins metabolism, Tumor Microenvironment, Cyclins genetics, Cyclins metabolism, Neoplasms genetics
- Abstract
CDK4, along with its regulatory subunit, cyclin D, drives the transition from G1 to S phase, during which DNA replication and metabolic activation occur. In this canonical pathway, CDK4 is essentially a transcriptional regulator that acts through phosphorylation of retinoblastoma protein (RB) and subsequent activation of the transcription factor E2F, ultimately triggering the expression of genes involved in DNA synthesis and cell cycle progression to S phase. In this review, we focus on the newly reported functions of CDK4, which go beyond direct regulation of the cell cycle. In particular, we describe the extranuclear roles of CDK4, including its roles in the regulation of metabolism, cell fate, cell dynamics and the tumor microenvironment. We describe direct phosphorylation targets of CDK4 and decipher how CDK4 influences these physiological processes in the context of cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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3. Apoptotic Effect of Isoimpertorin via Inhibition of c-Myc and SIRT1 Signaling Axis.
- Author
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Ko, Hwan-Joo, Park, Su-Yeon, Sim, Deok Yong, Kim, Sung-Hoon, Hur, Soyoung, Lee, Jang-Hoon, and Kim, Youngchul
- Subjects
LIVER cancer ,DRUG target ,CYCLIN-dependent kinases ,PROTEASOME inhibitors ,CYCLINS - Abstract
Though Isoimperatorin from Angelicae dahuricae is known to have antiviral, antidiabetic, anti-inflammatory and antitumor effects, its underlying antitumor mechanism remains elusive so far. Hence, the apoptotic mechanism of Isoimperatorin was explored in hepatocellular carcinomas (HCCs). In this study, Isoimperatorin inhibited the viability of Huh7 and Hep3B HCCs and increased the subG1 apoptotic portion and also abrogated the expression of pro-poly-ADP ribose polymerase (pro-PARP) and pro-caspase 3 in Huh7 and Hep3B cells. Also, Isoimperatorin abrogated the expression of cyclin D1, cyclin E1, CDK2, CDK4, CDK6 and increased p21 as G1 phase arrest-related proteins in Huh7 and Hep3B cells. Interestingly, Isoimperatorin reduced the expression and binding of c-Myc and Sirtuin 1 (SIRT1) by Immunoprecipitation (IP), with a binding score of 0.884 in Huh7 cells. Furthermore, Isoimperatorin suppressed the overexpression of c-Myc by the proteasome inhibitor MG132 and also disturbed cycloheximide-treated c-Myc stability in Huh7 cells. Overall, these findings support the novel evidence that the pivotal role of c-Myc and SIRT1 is critically involved in Isoimperatorin-induced apoptosis in HCCs as potent molecular targets in liver cancer therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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4. Cyclin D1 expression in penile cancer.
- Subjects
CYCLINS ,PENILE cancer ,CELL cycle proteins ,SIGNAL peptides ,MEDICAL sciences - Abstract
A research paper titled "Cyclin D1 expression in penile cancer" was recently published in Oncotarget's Volume 15. The study, conducted by researchers from various universities in Brazil, aimed to analyze the expression of cyclin D1 in patients with penile cancer (PC) and determine its correlation with clinical and histopathological features. The study involved 100 PC patients and found that the absence of cyclin D1 expression was associated with HPV-positive histological subtypes, while its expression was associated with high-grade tumors, histological subtype, presence of sarcomatoid transformation, and perineural invasion. The researchers suggest that cyclin D1 may be a potential biomarker for PC, particularly for poorer prognosis. [Extracted from the article]
- Published
- 2024
5. Skp2-Cyclin A Interaction Is Necessary for Mitotic Entry and Maintenance of Diploidy.
- Author
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Vasavan, Biju, Das, Nilanjana, Kahnamouei, Paria, Trombley, Chantelle, and Swan, Andrew
- Subjects
- *
DIPLOIDY , *CELL cycle , *UBIQUITIN ligases , *CYCLINS , *POLYPLOIDY , *MITOSIS , *UBIQUITINATION - Abstract
[Display omitted] • Skp2 functions with the mitotic Cyclin A-Cdk1 complex to promote entry into mitosis. • Skp2 and cyclin A physically interact in Drosophila and Skp2 is required to maintain cyclin A levels. • By-pass of mitosis in Skp2 mutants results in polyploidy. • Polyploid Skp2 mutant cells that enter mitosis trigger checkpoints that arrest or delay mitosis or promote apoptosis. Skp2, the substrate recognition component of the SCFSkp2 ubiquitin ligase, has been implicated in the targeted destruction of a number of key cell cycle regulators and the promotion of S-phase. One of its critical targets is the Cyclin dependent kinase (Cdk) inhibitor p27, and indeed the overexpression of Skp2 in a number of cancers is directly correlated with the premature degradation of p27. Skp2 was first identified as a protein that interacts with Cyclin A in transformed cells, but its role in this complex has remained unclear. In this paper, we demonstrate that Skp2 interacts with Cyclin A in Drosophila and is required to maintain Cyclin A levels and permit mitotic entry. Failure of mitotic entry in Skp2 mutant cells results in polyploidy. If these cells enter mitosis again they are unable to properly segregate their chromosomes, leading to checkpoint dependent cell cycle arrest or apoptosis. Thus, Skp2 is required for mitosis and for maintaining diploidy and genome stability. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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6. Highlighting the Major Role of Cyclin C in Cyclin-Dependent Kinase 8 Activity through Molecular Dynamics Simulations.
- Author
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Ziada, Sonia, Diharce, Julien, Serillon, Dylan, Bonnet, Pascal, and Aci-Sèche, Samia
- Subjects
MOLECULAR dynamics ,CYCLINS ,CYCLIN-dependent kinases ,PROTEIN kinase C ,PROTEIN-protein interactions - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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7. Overexpression of cyclin F/CCNF as an independent prognostic factor for poor survival in clear cell renal cell carcinoma.
- Author
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Kwiatkowski, Maciej, Krajewski, Adrian, Durślewicz, Justyna, Buchholz, Karolina, Grzanka, Dariusz, Gagat, Maciej, Zabrzyński, Jan, and Klimaszewska-Wiśniewska, Anna
- Subjects
RENAL cell carcinoma ,CYCLINS ,PROGNOSIS ,GENE expression ,TUMOR-infiltrating immune cells - Abstract
Cyclin F (encoded by CCNF gene) has been reported to be implicated in the pathobiology of several human cancers. However, its potential clinical significance in clear cell renal cell carcinoma (ccRCC) remains unknown. The present study aimed to evaluate the potential significance of cyclin F, assessed by immunohistochemical (IHC) staining and molecular (bioinformatics) techniques, as a prognostic marker in ccRCC in relation to clinicopathological features and outcomes. IHC staining was performed using two independent ccRCC tissue array cohorts, herein called tissue macroarray (TMA)_1 and tissue microarray (TMA)_2, composed of 108 ccRCCs and 37 histologically normal tissues adjacent to the tumor (NAT) and 192 ccRCCs and 16 normal kidney samples, respectively. The mRNA expression data were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) public datasets, followed by bioinformatics analysis of biological mechanisms underlying prognosis. The relationship between immune cell infiltration level and CCNF expression in ccRCC was investigated using the Tumor Immune Estimation Resource 2.0 (TIMER2) and Gene Expression Profiling Interactive Analysis 2 (GEPIA2). Cyclin F expression was significantly elevated in ccRCC lesions compared to both NAT and normal renal tissues. Likewise, CCNF mRNA was markedly increased in ccRCCs relative to non-cancerous tissues. In all analyzed cohorts, tumors with features of more aggressive behavior were more likely to display cyclin F/CCNF-high expression than low. Furthermore, patients with high cyclin F/CCNF expression had shorter overall survival (OS) times than those with low expression. In addition, multivariable analysis revealed that cyclin F/CCNF-high expression was an independent prognostic factor for poor OS in ccRCC. Enrichment analysis for mechanistically relevant processes showed that CCNF and its highly correlated genes initiate the signaling pathways that eventually result in uncontrolled cell proliferation. CCNF expression was also correlated with immune cell infiltration and caused poor outcomes depending on the abundance of tumor-infiltrating immune cells in ccRCC. Our findings suggest that cyclin F/CCNF expression is likely to have an essential role in ccRCC pathobiology through regulating multiple oncogenic signaling pathways and affecting the tumor immune microenvironment and may serve as prognostic biomarker and promising therapeutic target in ccRCC. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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8. Chemotherapeutic potential of betanin/capecitabine combination targeting colon cancer: experimental and bioinformatic studies exploring NFκB and cyclin D1 interplay.
- Author
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Ahmed, Rehab, Zaitone, Sawsan A., Abdelmaogood, Asmaa K. K., Atef, Huda M., Soliman, Mona F. M., Badawy, Alaa M., Ali, Howaida S., Zaid, AbdelNaser, Mokhtar, Hatem I., Elabbasy, Lamiaa M., Kandil, Emad, Yosef, Asmaa Mokhtar, and Mahran, Rama I.
- Subjects
COLON cancer ,CHEMICAL carcinogenesis ,CYCLINS ,BIOLOGICAL assay ,CANCER chemotherapy - Abstract
Introduction: Betanin (C24H26N2O13) is safe to use as food additives approved by the FDA with anti-inflammatory and anticancer effects in many types of cancer cell lines. The current experiment was designed to test the chemotherapeutic effect of the combination of betanin with the standard chemotherapeutic agent, capecitabine, against chemically induced colon cancer in mice. Methods: Bioinformatic approachwas designed to get information about the possible mechanisms through which the drugs may control cancer development. Five groups of mice were assigned as, (i) saline, (ii) colon cancer, (iii) betanin, (iv) capecitabine and (v) betanin/capecitabine. Drugs were given orally for a period of six weeks. Colon tissues were separated and used for biological assays and histopathology. Results: In addition, the mRNA expression of TNF-a (4.58-fold), NFκB (5.33-fold), IL-1β (4.99-fold), cyclin D1 (4.07-fold), and IL-6 (3.55-fold) and protein levels showed several folds increases versus the saline group. Tumor histopathology scores in the colon cancer group (including cryptic distortion and hyperplasia) staining demonstrated poor mucin content (33% of the saline group). These pathologic manifestations were reduced remarkably in betanin/capecitabine group. Conclusion: Collectively, our findings demonstrated the usefulness of betanin/capecitabine combination in targeting colon cancer and highlighted that betanin is a promising adjuvant therapy to capecitabine in treating colon cancer patients. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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9. The role of D3-type cyclins is related to cytokinin and the bHLH transcription factor SPATULA in Arabidopsis gynoecium development
- Author
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Cerbantez-Bueno, Vincent E., Serwatowska, Joanna, Rodríguez-Ramos, Carolina, Cruz-Valderrama, J. Erik, and de Folter, Stefan
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- 2024
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10. Cyclin A1 (CCNA1) inhibits osteoporosis by suppressing transforming growth factor-beta (TGF-beta) pathway in osteoblasts.
- Author
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Du, Xiao, Zang, Chuanyi, and Wang, Qinglei
- Subjects
OSTEOCLASTS ,BONE morphogenetic proteins ,OSTEOPOROSIS ,CYCLINS ,GENE expression ,OSTEOBLASTS - Abstract
Background: Osteoporosis is a genetic disease caused by the imbalance between osteoblast-led bone formation and osteoclast-induced bone resorption. However, further gene-related pathogenesis remains to be elucidated. Methods: The aberrant expressed genes in osteoporosis was identified by analyzing the microarray profile GSE100609. Serum samples of patients with osteoporosis and normal group were collected, and the mRNA expression of candidate genes was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The mouse cranial osteoblast MC3T3-E1 cells were treated with dexamethasone (DEX) to mimic osteoporosis in vitro. Alizarin Red staining and alkaline phosphatase (ALP) staining methods were combined to measure matrix mineralization deposition of MC3T3-E1 cells. Meanwhile, the expression of osteogenesis related genes including alkaline phosphatase (ALP), osteocalcin (OCN), osteopontin (OPN), Osterix, and bone morphogenetic protein 2 (BMP2) were evaluated by qRT-PCR and western blotting methods. Then the effects of candidate genes on regulating impede bone loss caused by ovariectomy (OVX) in mice were studied. Results: Cyclin A1 (CCNA1) was found to be significantly upregulated in serum of osteoporosis patients and the osteoporosis model cells, which was in line with the bioinformatic analysis. The osteogenic differentiation ability of MC3T3-E1 cells was inhibited by DEX treatment, which was manifested by decreased Alizarin Red staining intensity, ALP staining intensity, and expression levels of ALP, OCN, OPN, Osterix, and BMP2. The effects of CCNA1 inhibition on regulating osteogenesis were opposite to that of DEX. Then, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that genes negatively associated with CCNA1 were enriched in the TGF-beta signaling pathway. Inhibitor of TGF-beta signaling pathway partly reversed osteogenesis induced by suppressed CCNA1. Furthermore, suppressed CCNA1 relieved bone mass of OVX mice in vivo. Conclusion: Downregulation of CCNA1 could activate TGF-beta signaling pathway and promote bone formation, thus playing a role in treatment of osteoporosis. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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11. The methyltransferase N6AMT1 participates in the cell cycle by regulating cyclin E levels.
- Author
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Mutso, Margit, Brūmele, Baiba, Serova, Evgeniia, Väärtnõu, Fred, Suija, Mihkel, and Kurg, Reet
- Subjects
CELL cycle ,CELL cycle regulation ,CYCLINS ,METHYLTRANSFERASES ,CELL proliferation ,CELL analysis - Abstract
The methyltransferase N6AMT1 has been associated with the progression of different pathological conditions, such as tumours and neurological malfunctions, but the underlying mechanism is not fully understood. Analysis of N6AMT1-depleted cells revealed that N6AMT1 is involved in the cell cycle and cell proliferation. In N6AMT1-depleted cells, the cell doubling time was increased, and cell progression out of mitosis and the G0/G1 and S phases was disrupted. It was discovered that in N6AMT1-depleted cells, the transcription of cyclin E was downregulated, which indicates that N6AMT1 is involved in the regulation of cyclin E transcription. Understanding the functions and importance of N6AMT1 in cell proliferation and cell cycle regulation is essential for developing treatments and strategies to control diseases that are associated with N6AMT1. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
12. Overexpression of Alpha-1 Antitrypsin Increases the Proliferation of Mesenchymal Stem Cells by Upregulation of Cyclin D1.
- Author
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Wolf, Bryan, Muralidharan, Prasanth, Lee, Michael Y., Hua, Wei, Green, Erica, Wang, Hongjun, and Strange, Charlie
- Subjects
MESENCHYMAL stem cells ,CELL proliferation ,CYCLINS ,TRYPSIN inhibitors ,CELL cycle ,WNT signal transduction - Abstract
Alpha-1 antitrypsin-overexpressing mesenchymal stromal/stem cells (AAT-MSCs) showed improved innate properties with a faster proliferation rate when studied for their protective effects in mouse models of diseases. Here, we investigated the potential mechanism(s) by which AAT gene insertion increases MSC proliferation. Human bone marrow-derived primary or immortalized MSCs (iMSCs) or AAT-MSCs (iAAT-MSCs) were used in the study. Cell proliferation was measured by cell counting and cell cycle analysis. Possible pathways involved in the pro-proliferation effect of AAT were investigated by measuring mRNA and protein expression of key cell cycle genes. Interval cell counting showed increased proliferation in AAT-MSCs or iAAT-MSCs compared to their corresponding MSC controls. Cell cycle analysis revealed more cells progressing into the S and G2/M phases in iAAT-MSCs, with a notable increase in the cell cycle protein, Cyclin D1. Moreover, treatment with Cyclin D1 inhibitors showed that the increase in proliferation is due to Cyclin D1 and that the AAT protein is upstream and a positive regulator of Cyclin D1. Furthermore, AAT's effect on Cyclin D1 is independent of the Wnt signaling pathway as there were no differences in the expression of regulatory proteins, including GSK3β and β-Catenin in iMSC and iAAT-MSCs. In summary, our results indicate that AAT gene insertion in an immortalized MSC cell line increases cell proliferation and growth by increasing Cyclin D1 expression and consequently causing cells to progress through the cell cycle at a significantly faster rate. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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13. The oscillation of mitotic kinase governs cell cycle latches in mammalian cells.
- Author
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Dragoi, Calin-Mihai, Kaur, Ekjot, Barr, Alexis R., Tyson, John J., and Novák, Béla
- Subjects
MAMMALIAN cell cycle ,CELL cycle proteins ,OSCILLATIONS ,CYCLINS - Abstract
The mammalian cell cycle alternates between two phases - S-G2-M with high levels of A- and B-type cyclins (CycA and CycB, respectively) bound to cyclin-dependent kinases (CDKs), and G1 with persistent degradation of CycA and CycB by an activated anaphase promoting complex/cyclosome (APC/C) bound to Cdh1 (also known as FZR1 in mammals; denoted APC/C:Cdh1). Because CDKs phosphorylate and inactivate Cdh1, these two phases are mutually exclusive. This 'toggle switch' is flipped from G1 to S by cyclin-E bound to a CDK (CycE:CDK), which is not degraded by APC/C:Cdh1, and from M to G1 by Cdc20-bound APC/C (APC/C:Cdc20), which is not inactivated by CycA:CDK or CycB:CDK. After flipping the switch, cyclin E is degraded and APC/C:Cdc20 is inactivated. Combining mathematical modelling with single-cell timelapse imaging, we show that dysregulation of CycB:CDK disrupts strict alternation of the G1-S and M-G1 switches. Inhibition of CycB:CDK results in Cdc20-independent Cdh1 'endocycles', and sustained activity of CycB:CDK drives Cdh1-independent Cdc20 endocycles. Our model provides a mechanistic explanation for how wholegenome doubling can arise, a common event in tumorigenesis that can drive tumour evolution. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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14. Regnase-2 inhibits glioblastoma cell proliferation.
- Author
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Sowinska, Weronika, Wawro, Mateusz, Kochan, Jakub, Solecka, Aleksandra, Polak, Jarosław, Kwinta, Borys, and Kasza, Aneta
- Subjects
INHIBITION of cellular proliferation ,CANCER cell proliferation ,GLIOBLASTOMA multiforme ,GLIOMAS ,CYCLINS - Abstract
Regnase-2 (Reg-2/MCPIP2/ZC3H12B) is uniquely expressed at a high level in the healthy brain and down-regulated in samples from patients with glioma, reaching the lowest level in high-grade glioblastoma multiforme (GBM). This RNase is involved in the regulation of neuroinflammation through the degradation of IL-6 and IL-1 mRNAs, key pro-inflammatory cytokines for GBM pathology. Reg-2 is a strong inhibitor of the proliferation of human glioblastoma cell lines and blocks their potential to form colonies. Here, we describe that overexpression of Reg-2 stalls glioblastoma cells in the G1 phase of the cell cycle and reduces the level of transcripts implicated in cell cycle progression. These newly identified targets include CCND1, CCNE1, CCNE2, CCNA2, CCNB1, and CCNB2, encoding the cyclins as well as AURKA and PLK1, encoding two important mitosis regulators. By RNA immunoprecipitation we confirmed the direct interaction of Reg-2 with the investigated transcripts. We also tested mRNA regions involved in their interaction with Reg-2 on the example of CCNE2. Reg-2 interacts with the 3'UTR of CCNE2 in a dose-dependent manner. In conclusion, our results indicate that Reg-2 controls key elements in GBM biology by restricting neuroinflammation and inhibiting cancer cell proliferation. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
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