Cyclin-dependent Kinase Subunit Research Articles

Human promoter directionality is determined by transcriptional initiation and the opposing activities of INTS11 and CDK9.

RNA polymerase II (RNAPII) transcription initiates bidirectionally at many human protein-coding genes. Sense transcription usually dominates and leads to messenger RNA production, whereas antisense transcription rapidly terminates. The basis for this directionality is not fully understood. Here, we show that sense transcriptional initiation is more efficient than in the antisense direction, which establishes initial promoter directionality. After transcription begins, the opposing functions of the endonucleolytic subunit of Integrator, INTS11, and cyclin-dependent kinase 9 (CDK9) maintain directionality. Specifically, INTS11 terminates antisense transcription, whereas sense transcription is protected from INTS11-dependent attenuation by CDK9 activity. Strikingly, INTS11 attenuates transcription in both directions upon CDK9 inhibition, and the engineered recruitment of CDK9 desensitises transcription to INTS11. Therefore, the preferential initiation of sense transcription and the opposing activities of CDK9 and INTS11 explain mammalian promoter directionality.

Human promoter directionality is determined by transcriptional initiation and the opposing activities of INTS11 and CDK9

RNA polymerase II (RNAPII) transcription initiates bidirectionally at many human protein-coding genes. Sense transcription usually dominates and leads to messenger RNA production, whereas antisense transcription rapidly terminates. The basis for this directionality is not fully understood. Here, we show that sense transcriptional initiation is more efficient than in the antisense direction, which establishes initial promoter directionality. After transcription begins, the opposing functions of the endonucleolytic subunit of Integrator, INTS11, and cyclin-dependent kinase 9 (CDK9) maintain directionality. Specifically, INTS11 terminates antisense transcription, whereas sense transcription is protected from INTS11-dependent attenuation by CDK9 activity. Strikingly, INTS11 attenuates transcription in both directions upon CDK9 inhibition, and the engineered recruitment of CDK9 desensitises transcription to INTS11. Therefore, the preferential initiation of sense transcription and the opposing activities of CDK9 and INTS11 explain mammalian promoter directionality.

Human promoter directionality is determined by transcriptional initiation and the opposing activities of INTS11 and CDK9

RNA polymerase II (RNAPII) transcription initiates bidirectionally at many human protein-coding genes. Sense transcription usually dominates and leads to messenger RNA production, whereas antisense transcription rapidly terminates. The basis for this directionality is not fully understood. Here, we show that sense transcriptional initiation is more efficient than in the antisense direction, which establishes initial promoter directionality. After transcription begins, the opposing functions of the endonucleolytic subunit of Integrator, INTS11, and cyclin-dependent kinase 9 (CDK9) maintain directionality. Specifically, INTS11 terminates antisense transcription, whereas sense transcription is protected from INTS11-dependent attenuation by CDK9 activity. Strikingly, INTS11 attenuates transcription in both directions upon CDK9 inhibition, and the engineered recruitment of CDK9 desensitises transcription to INTS11. Therefore, the preferential initiation of sense transcription and the opposing activities of CDK9 and INTS11 explain mammalian promoter directionality.

Genome-Wide Identification and Evolutionary and Expression Analyses of the Cyclin B Gene Family in Brassica napus.

Cyclin B (CYCB) is a regulatory subunit of cyclin-dependent kinase (CDK), the concentration of which fluctuates to regulate cell cycle progression. Extensive studies have been performed on cyclins in numerous species, yet the evolutionary relationships and biological functions of the CYCB family genes in Brassica napus remain unclear. In this study, we identified 299 CYCB genes in 11 B. napus accessions. Phylogenetic analysis suggests that CYCB genes could be divided into three subfamilies in angiosperms and that the CYCB3 subfamily members may be a newer group that evolved in eudicots. The expansion of BnaCYCB genes underwent segmental duplication and purifying selection in genomes, and a number of drought-responsive and light-responsive cis-elements were found in their promoter regions. Additionally, expression analysis revealed that BnaCYCBs were strongly expressed in the developing seed and silique pericarp, as confirmed by the obviously reduced seed size of the mutant cycb3;1 in Arabidopsis thaliana compared with Col-0. This study provides a comprehensive evolutionary analysis of CYCB genes as well as insight into the biological function of CYCB genes in B. napus.

Prognostic significance of cyclin-dependent kinase subunit 2 (CKS2) in malignant tumours: a meta-analysis and bioinformatic analysis

ObjectivesThis study aimed to systematically elucidate the prognostic significance of cyclin-dependent kinase subunit 2 (CKS2) expression in various cancers and its correlation with their clinicopathological characteristics.DesignIn this meta-analysis and bioinformatic...

Global trends and hotspots in Cyclin-dependent Kinase Subunit 2 research from 1999 to 2022: A bibliometric and visualized analysis.

Cyclin-dependent Kinase Subunit 2 is a protein closely related to the regulation of the cell cycle. In recent years, there has been an increasing number of research articles on this topic. However, there is a lack of comprehensive synthesis and evaluation in the field of CKS2 research. This study aims to summarize and visualize the literature distribution, research hotspots, and development trends of CKS2 based on bibliometric methods. Publications from 1999 to 2022 were extracted from the Web of Science. Citespace was used to analyze the relevant information of each article. A total of 138 publications focused on CKS2 showed a positive growth trend from 1999 to 2022 and were published by 27 countries. The most prolific countries are China and the USA. The most prolific institution is Scripps Research Institute. The most prolific author is Steven I. Reed from Scripps Research Institute. The most cited article is published by Todd R Golub. The most cited author is Hanna-Stina Martinsson-Ahlzen. The journal with the most published articles is International Journal of Oncology. The high frequency keywords suggest that expression and function of CKS2 in cancer are dominated topics. The clusters and burst words suggest that expression and function of CKS2 still active in the future. The results of this bibliometric analysis provide information on the state and trends in CKS2 from 1999 to 2022. It is helpful for scholars to pinpoint hot issues and discover new areas of study.

Aberrant expression of CKS2 induced by ELK1 contributes to malignant progression of pancreatic cancer.

Cyclin-dependent kinase subunit 2 (CKS2) has been reported to promote various malignancies. This study investigated the functional role of CKS2 in pancreatic cancer (PC). An analysis of abnormally expressed genes and their prognostic value for PC was performed by using the Gene Expression Profiling Interactive Analysis (GEPIA) database and performing immunohistochemical staining on 64 samples of tumor tissue. CCK-8 assays, EdU staining, colony formation assays, flow cytometry, and a xenograft tumor model were used to analyze the biological function of CKS2 in PC. Our results revealed that CKS2 was expressed at significantly higher levels in PC tissues than in adjacent normal tissues, and a high level of CKS2 expression was associated with a poor prognosis for patients with PC. Moreover, functional assays revealed that CKS2 knockdown suppressed cell proliferation, induced cell cycle S phase, G2/M phase arrest, and apoptosis in vitro, and also reduced tumor growth in vivo. In addition, CKS2 knockdown increased the levels of Bax, caspase-3, P53, P21, and GADD45α expression, but decreased Bcl-2, Cyclin B1, CDK1, Cyclin A, and Cdc25C expression. CKS2 overexpression produced the opposite effects of CKS2 knockdown. Furthermore, we found that ELK1 protein regulated transcription of the CKS2 gene. In conclusion, our findings suggest that CKS2 expression is regulated by ELK1, which could possibly serve as prognostic indicator and therapeutic target for PC.

Abstract 1427: NQO1/c-Fos/CKS1 signaling pathway regulates cell cycle progression at the G2/M phase

Abstract Overexpression of NAD(P)H:quinone oxidoreductase 1 (NQO1) is associated with tumor cell proliferation and growth in several human cancer types. However, the molecular mechanisms underlying the activity of NQO1 in cell cycle progression are currently unclear. Here, we report a novel function of NQO1 in modulation of cyclin-dependent kinase subunit (CKS1), a cell cycle regulator, at the G2/M phase, through effects on the stability of c-Fos. We analyzed the roles of NQO1/c-Fos/CKS signaling pathway in cell cycle progression in cancer cells using synchronization of cell cycle and flow cytometry. The mechanisms of NQO1/c-Fos/CKS1-mediated regulation of cell cycle progression in cancer cells were studied by siRNA, overexpression system, reporter assay, co-immunoprecipitation, pull-down assay, microarray analysis, and CDK1 kinase assay. In addition, publicly available data sets and immunohistochemistry were used to investigate the correlation between NQO1 expression levels and clinicopathological features in cancer patients. Our results suggest that NQO1 directly interacts with the unstructured DNA-binding domain of c-Fos implicated in proliferation, differentiation, development and survival of cancer and inhibits its proteasome-mediated degradation, thereby inducing CKS1 expression and regulating cell cycle progression at the G2/M phase. Notably, NQO1 deficiency in human cancer cell lines led to suppression of c-Fos-mediated CKS1 expression and cell cycle progression. Consistent with this finding, high NQO1 expression was correlated with increased CKS1 and poor prognosis in cancer patients. Our collective results support a novel regulatory role of NQO1 in the mechanism of cell cycle progression at the G2/M phase through effects on c-Fos/CKS1 signaling pathway in cancer. Citation Format: Eun-Taex Oh, Ha Gyeong Kim, Yunmi Cho, Heon Joo Park. NQO1/c-Fos/CKS1 signaling pathway regulates cell cycle progression at the G2/M phase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1427.

The CKS1/CKS2 Proteostasis Axis Is Crucial to Maintain Hematopoietic Stem Cell Function.

Long-term hematopoietic stem cells are rare, highly quiescent stem cells of the hematopoietic system with life-long self-renewal potential and the ability to transplant and reconstitute the entire hematopoietic system of conditioned recipients. Most of our understanding of these rare cells has relied on cell surface identification, epigenetic, and transcriptomic analyses. Our knowledge of protein synthesis, folding, modification, and degradation-broadly termed protein homeostasis or "proteostasis"-in these cells is still in its infancy, with very little known about how the functional state of the proteome is maintained in hematopoietic stem cells. We investigated the requirement of the small phospho-binding adaptor proteins, the cyclin-dependent kinase subunits (CKS1 and CKS2), for maintaining ordered hematopoiesis and long-term hematopoietic stem cell reconstitution. CKS1 and CKS2 are best known for their roles in p27 degradation and cell cycle regulation, and by studying the transcriptome and proteome of Cks1 -/- and Cks2 -/- mice, we demonstrate regulation of key signaling pathways that govern hematopoietic stem cell biology including AKT, FOXO1, and NFκB, together balancing protein homeostasis and restraining reactive oxygen species to ensure healthy hematopoietic stem cell function.

Protein-RNA interactions of FMRP and CCND1: Implications of regulation in neurogenesis.

While originally discovered in the 1960s, adult neurogenesis, the production of mature neurons from neuronal stem cells in adults, has become largely accepted by the field only in the 1990s. Thus, the detailed mechanisms of its regulation remain elusive, requiring further characterization of the protein players involved in this process. Cyclin-D1, a regulatory subunit of cyclin-dependent kinases involved in monitoring entry into the cell cycle, has been identified as a key factor in adult neurogenesis and is encoded by the CCND1 gene. Another identified component of this process is the Fragile X messenger ribonucleoprotein (FMRP), an RNA-binding protein associated with translational regulation. Interestingly, FMRP has been shown to regulate cyclin-D1 expression, emphasizing a potential interplay between FMRP function and cyclin-D1 expression in neurons. FMRP has shown high affinity binding for guanine quadruplex (GQ) forming RNAs. We identified that CCND1 mRNA has a G-rich region in its 3’-untranslated region that has the potential to form GQ structures, and thus possibly interacting with FMRP through the recognition of these structures. To elucidate the presence of a GQ in the CCND1 mRNA, we used biophysical methods, such as 1H NMR, UV thermal denaturation, CD spectroscopy, and native polyacrylamide gel electrophoresis (PAGE). This study effectively characterizes a GQ in the 3’UTR of the CCND1 mRNA and its interactions with FMRP, providing insight on additional regulatory mechanisms of adult neurogenesis and guiding development of novel therapeutic methods.

Lack of Cyclin E1 in hepatocytes aggravates ethanol-induced liver injury and hepatic steatosis in experimental murine model of acute and chronic alcohol-associated liver disease

BackgroundCyclin E1 is the regulatory subunit of cyclin-dependent kinase 2 (Cdk2) and one of the central players in cell cycle progression. We recently showed its crucial role for initiation of liver fibrosis and hepatocarcinogenesis. In the present study, we investigated the role of Cyclin E1 in the development of alcohol-associated liver disease (ALD). MethodsMice with constitutive (E1−/−), hepatocyte-specific (Cyclin E1Δhepa), or intestinal-epithelial-cell-specific (Cyclin E1ΔIEC) inactivation of Cyclin E1 and corresponding wild type littermate controls (WT) were administered either a Lieber-DeCarli ethanol diet (LDE) for 3 weeks or acute ethanol binges (6 g/kg) through oral gavage. Serum parameters of liver functionality were measured; hepatic tissues were collected for biochemical and histological analyses. ResultsThe administration of acute EtOH binge and chronic LDE diet to E1−/− mice enhanced hepatic steatosis, worsened liver damage and triggered body weight loss. Similarly, in the acute EtOH binge model, Cyclin E1Δhepa mice revealed a significantly worsened liver phenotype. In contrast, inactivation of Cyclin E1 only in intestinal epithelial cell (IECs)did not lead to any significant changes in comparison to WT mice after acute EtOH challenge. Remarkably, both acute and chronic EtOH administration in E1−/− animals resulted in increased levels of ADH and decreased expression of ALDH1/2. The additional application of a pan-Cdk inhibitor (S-CR8) further promoted liver damage in EtOH-treated WT mice. ConclusionOur data point to a novel unexpected role of Cyclin E1 in hepatocytes for alcohol metabolism, which seems to be independent of the canonical Cyclin E1/Cdk2 function as a cell cycle regulator.

Cyclin A–CDK1 suppresses the expression of the CDK1 activator CDC25A to safeguard timely mitotic entry

Cyclin A and CDC25A are both activators of cyclin-dependent kinases (CDKs): cyclin A acts as an activating subunit of CDKs and CDC25A a phosphatase of the inhibitory phosphorylation sites of the CDKs. In this study, we uncovered an inverse relationship between the two CDK activators. As cyclin A is an essential gene, we generated a conditional silencing cell line using a combination of CRISPR-Cas9 and degron-tagged cyclin A. Destruction of cyclin A promoted an acute accumulation of CDC25A. The increase of CDC25A after cyclin A depletion occurred throughout the cell cycle and was independent on cell cycle delay caused by cyclin A deficiency. Moreover, we determined that the inverse relationship with cyclin A was specific for CDC25A and not for other CDC25 family members or kinases that regulate the same sites in CDKs. Unexpectedly, the upregulation of CDC25A was mainly caused by an increase in transcriptional activity instead of a change in the stability of the protein. Reversing the accumulation of CDC25A severely delayed G2-M in cyclin A-depleted cells. Taken together, these data provide evidence of a compensatory mechanism involving CDC25A that ensures timely mitotic entry at different levels of cyclin A.

Cyclin-Dependent Kinase Subunit 2 (CKS2) as a Prognostic Marker for Stages I-III Invasive Non-Mucinous Lung Adenocarcinoma and Its Role in Affecting Drug Sensitivity.

With the aim of improving the prognosis of patients with lung adenocarcinoma (LUAD), we identified the biomarker related to the sensitivity of patients to chemotherapy drugs and explored the potential mechanisms. As a cell cycle-related protein, CKS2 has an essential role to play in tumor progression and prognosis. CKS2 expression was measured using TCGA RNA-sequencing data and immunohistochemistry. The sensitivity data of tumor cells to chemotherapeutic drugs for lung cancer was acquired from the Cancer Therapeutics Response Portal (CTRP) database. A range of bioinformatics methods was used to explore the mechanisms of CKS2 upregulation. The biological functions of CKS2 were predicted using GO and KEGG enrichment analysis, as well as GSEA. CKS2 expression was up-regulated in stages I–III invasive non-mucinous lung adenocarcinoma and varied significantly between various histological subtypes. High CKS2 expression worsened the prognosis of patients. The CKS2 expression level was linked to the sensitivity of LUAD cells to carboplatin and paclitaxel. CKS2 upregulation was associated with the immune microenvironment, mRNA methylation, and competing endogenous RNAs (ceRNAs). CKS2 can serve as a diagnostic and prognostic biomarker for stages I–III invasive non-mucinous lung adenocarcinoma and modulate the effect of paclitaxel and carboplatin by regulating microtubule binding and influencing carboplatin binding to DNA.

Prognostic significance of CKS2 and CD47 expression in patients with gastric cancer who underwent radical gastrectomy.

To investigate the protein expression levels of cyclin-dependent kinase subunit 2 (CKS2) and the cluster of differentiation (CD) 47 in gastric cancer (GC) and their clinical significance. A total of 126 GC patients who underwent radical resection were selected as study subjects. Additionally, 32 patients with benign gastric tumour, 42 patients with low-grade intraepithelial neoplasia (LGIEN), and 49 patients with high-grade intraepithelial neoplasia (HGIEN) who underwent surgery were selected as the control groups. Immunohistochemistry was used to detect the expression of CKS2 and CD47 in surgical specimens. We statistically analysed the clinical significance of the expression of the two factors. (1) The positivity rates for CKS2 in benign gastric tumour tissue, LGIEN tissue, HGIEN tissue, and GC tissue gradually increased, that is, 6.3% (2/32), 30.9% (13/42), 38.8% (19/49), and 60.3% (76/126), respectively, and the positivity rates for CD47 were 18.8% (6/32), 38.1% (16/42), 46.9% (23/49), and 65.9% (83/126), respectively. (2) High expression of CKS2 and CD47 were associated with tumour diameter, Lauren classification, number of lymph node metastases, and TNM stage. In addition, the immunohistochemical scores for CKS2 and CD47 were positively correlated (r=.625, P=.000). (3) The median follow-up time of 126 patients was 46.5months, and the overall survival (OS) rate was 40.5% (51/126). Survival analysis showed that compared with that in the CKS2 (-) group, the OS rate for patients in the CKS2 (+) group was significantly worse and that compared with the CD47 (-) group, the CD47 (+) group had significantly worse OS (30.1% vs 60.5%, χ2 =15.67, P=.000). (4) The OS rates of CKS2 (+) CD47 (+) group, CKS2 (+) CD47 (-) group, CKS2 (-) CD47 (+) group, and CKS2 (-) CD47 (-) group were 20.0% (13/65), 58.3% (7/12), 57.1% (8/14), 65.7% (23/35), respectively, the prognosis of patients in CKS2 (+) CD47 (+) group was significantly poor. High expression levels of CKS2 and CD47 were closely related to the occurrence of GC and can be used as independent risk factors to assess the prognosis of patients.

Cyclin E1 in Murine and Human Liver Cancer: A Promising Target for Therapeutic Intervention during Tumour Progression

Simple SummaryThe cell cycle regulator Cyclin E1 is a key mediator and biomarker of liver cancer progression in mice and man independent of its canonical interacting partner Cyclin-dependent kinase 2. Over-expression of Cyclin E1 during hepatocarcinogenesis modulates several distinct biological processes such as proliferation, DNA damage response, stemness, invasion and the tumour microenvironment. Interventional depletion of Cyclin E1 in the course of liver cancer progression significantly reduces tumour burden. In contrast, the expression of Cyclin-dependent kinase 2 is dispensable for the progression of liver cancer in mice and lacked diagnostic or prognostic value in patients. Thus, specific inhibition of Cyclin E1 expression represents a promising strategy for the treatment of liver cancer.Cyclin E1 (CCNE1) is a regulatory subunit of Cyclin-dependent kinase 2 (CDK2) and is thought to control the transition of quiescent cells into cell cycle progression. Recently, we identified CCNE1 and CDK2 as key factors for the initiation of hepatocellular carcinoma (HCC). In the present study, we dissected the contributions of CCNE1 and CDK2 for HCC progression in mice and patients. Therefore, we generated genetically modified mice allowing inducible deletion of Ccne1 or Cdk2. After initiation of HCC, using the hepatocarcinogen diethylnitrosamine (DEN), we deleted Ccne1 or Cdk2 and subsequently analysed HCC progression. The relevance of CCNE1 or CDK2 for human HCC progression was investigated by in silico database analysis. Interventional deletion of Ccne1, but not of Cdk2, substantially reduced the HCC burden in mice. Ccne1-deficient HCCs were characterised by attenuated proliferation, impaired DNA damage response and downregulation of markers for stemness and microinvasion. Additionally, the tumour microenvironment of Ccne1-deficient mice showed a reduction in immune mediators, myeloid cells and cancer-associated fibroblasts. In sharp contrast, Cdk2 was dispensable for HCC progression in mice. In agreement with our mouse data, CCNE1 was overexpressed in HCC patients independent of risk factors, and associated with reduced disease-free survival, a common signature for enhanced chromosomal instability, proliferation, dedifferentiation and invasion. However, CDK2 lacked diagnostic or prognostic value in HCC patients. In summary, CCNE1 drives HCC progression in a CDK2-independent manner in mice and man. Therefore, interventional inactivation of CCNE1 represents a promising strategy the treatment of liver cancer.

CKS2 Promotes the Growth in Non-Small-Cell Lung Cancer by Downregulating Cyclin-Dependent Kinase Inhibitor

Introduction/Objective: This study aimed to explore the expression of cyclin-dependent kinase subunit 2 (CKS2) in tissues and cells in non-small-cell lung cancer (NSCLC) and the function mechanism of CKS2 in NSCLC cell growth and tumorigensis. Methods: After transfecting NCI-H2170 cells with short-hair RNA (shRNA), an shCKS2 gene-silencing model was established. The cells were divided into a shRNA group and shNC group. For overexpression cell lines, we used the same method to establish the NCI-H2170-CKS2 cell lines. Cell Count Kit-8 assay and colony formation assay were used to determine cell viability and cell growth, respectively. Propidium iodide staining was used to determine cell cycle progression. The mRNA expression of CKS2 and protein expression of CKS2, p21, p53, and PTEN were determined by RT-qPCR and Western blotting, respectively. The expression of CKS2, p53, and Ki67 in tissues was determined by immunohistochemical stain. The in vivo tumorigenesis assays were used to determine the ability of CKS2 in tumor growth. Results: The results of RT-qPCR and Western blotting assay revealed that CKS2 upregulated expression in NSCLC tissues and cells. The results of the CCK-8 assay revealed that the shRNA group exhibited significantly lower cell viability and foci formation than the empty plasmid group, while CKS2 overexpression induces cell growth and cell cycle progression. The result of nude mice suggested that CKS2 knockdown expression suppressed tumorigenesis in the in vivo animal model. Conclusions: Our study suggests that CKS2 could be a biomarker in the progression and prognosis of NSCLC.

Endothelial overexpression of P25 causes premature vascular aging by promoting SIRT1 protein degradation

Background P25 is a regulatory subunit of cyclin-dependent kinase 5 (CDK5). The CDK5/P25 signaling is implicated in the regulation of SIRT1, a mammalian sirtuin with an important participation in aging. Hypothesis: Overexpression of endothelial p25 leads to premature vascular aging by regulating SIRT1 degradation. Aims: The aims of this study were to determine if overexpression of p25 in the vascular endothelium induces vascular aging by causing degradation of SIRT1 and increasing vascular contraction, oxidative stress and vascular senescence. Methods: The present study established a transgenic mouse model (EC-P25) with selective overexpression of P25 in endothelial cells. Aortas were obtained from 12- or 30-weeks old EC-p25 mice and control littermates for all experiments. Wire myography was performed in quiescent thoracic aorta with Mulvany-Halpern wire myograph system to measure isometric tension in the presence or absence of SIRT1 activators or inhibitors. Vascular senescence was evaluated using senescence-associated β-galactosidase (SA-β-gal) staining in aortae, whereas heamatoxylin-eosine (H & E) staining was performed on aortic sections to evaluate aortic wall hypertrophy. Melondialdehyde (MDA) concentration in aortic homogenates represented a measure of oxidative stress, and protein expression levels were measured by Western blotting. Results: EC-P25 mice showed increased vascular tone responsiveness to alpha-1-adrenergic receptor agonist phenylephrine (PE) compared to the control littermates suggesting that overexpression of p25 in the vascular endothelium has deleterious effects on vascular function. SA-β-gal staining was increased in EC-P25 mice when compared to the control group, demonstrating vascular senescence. H & E staining also showed aortic wall hypertrophy with an increase in aortic wall thickness in EC-P25 mice compared to control mice. MDA concentration was also higher in EC-P25 mice aorta than in the control group, implying increased oxidative stress. SIRT1 protein was found to be fragmented with increased levels of shorter fragments in EC-P25 aorta when compared to their control littermates, suggesting that, over-expression of P25 in the vascular endothelium regulates SIRT1 degradation leading to premature aging, adverse remodeling and loss of functional regulation. Conclusion: Overexpression of endothelial p25 may regulate vascular function by increasing vascular tone, aortic wall hypertrophy, oxidative stress and vascular aging leading to vascular disease. Additionally, a fragment of SIRT1 with enhanced deacetylase activity was detected in arteries of EC-P25 mice, whereas EX-527, a SIRT1 inhibitor, attenuated endothelium-dependent contractions. In conclusion, the results suggest that targeting CDK5/P25/SIRT1 signaling represents a promising strategy for ageing-associated vascular diseases.

Clinical significance of CCNE2 protein and mRNA expression in thyroid cancer tissues

PurposeThyroid carcinoma (TC) is the most common endocrinal malignancy worldwide. Cyclin E2 (CCNE2), a member of the cyclin family, acts as a regulatory subunit of cyclin-dependent kinases (CDKs). It controls the transition of quiescent cells into the cell cycle, regulates the G1/S transition, promotes DNA replication, and activates CDK2. This study explored the role and potential molecular mechanisms of CCNE2 expression in TC tissues. Material/methodsImmunohistochemistry was used to evaluate the CCNE2 protein expression levels in TC. High-throughput data on CCNE2 in TC were obtained from RNA sequencing (RNA-seq), microarray, and literature data. The CCNE2 expression levels in TC were comprehensively assessed through an integrated analysis. Analyses of Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein–protein interaction (PPIs) data facilitated the investigation of the relative molecular mechanisms of CCNE2 in TC. ResultsThe immunohistochemical experiment showed a significant increase in the expression of CCNE2 in the TC tissues. For 505 TC and 59 non-cancerous samples from RNA-seq data, the area under the curve (AUC) was 0.8016 (95% confidence interval [CI] 0.742–0.8612; p<0.001). With another 14 microarrays, the pool standard mean difference [SMD] was 1.01 (95% CI [0.82–1.19]). The pooled SMD of CCNE2 was 1.12 (95% CI [0.60–1.64]), and the AUC was 0.87 (95% CI [0.84–0.90]) for 1157 TC samples and 366 non-cancerous thyroid samples from all possible sources. Nine hub genes were upregulated in TC. ConclusionsA high expression of CCNE2 may lead to carcinogenesis and the development of TC.

Small Molecule CDK Inhibitors for the Therapeutic Management of Cancer.

Cyclin-dependent kinases (CDKs) are a group of multifunctional enzymes consisting of catalytic and regulatory subunits. The regulatory subunit, cyclin, remains dissociated under normal circumstances, and complexation of cyclin with the catalytic subunit of CDK leads to its activation for phosphorylation of protein substrates. The primary role of CDKs is in the regulation of the cell cycle. Retinoblastoma protein (Rb) is one of the widely investigated tumor suppressor protein substrates of CDK, which prevents cells from entering into cell-cycle under normal conditions. Phosphorylation of Rb by CDKs causes its inactivation and ultimately allows cells to enter a new cell cycle. Many cancers are associated with hyperactivation of CDKs as a result of mutation of the CDK genes or CDK inhibitor genes. Therefore, CDK modulators are of great interest to explore as novel therapeutic agents against cancer and led to the discovery of several CDK inhibitors to clinics. This review focuses on the current progress and development of anti-cancer CDK inhibitors from preclinical to clinical and synthetic to natural small molecules.

Antihypertensive drug telmisartan suppresses the proliferation of gastric cancer cells invitro and invivo.

Gastric cancer is one of the most common malignancies diagnosed worldwide. Telmisartan, an angiotensin receptor blocker (ARB), suppresses the proliferation of cancer cells and the growth of tumors through an unknown mechanism. To identify the mechanism, the present study was designed to evaluate the effects of telmisartan on gastric cancer cell lines and tumors invitro and invivo and the associated signaling molecules were identified. It was shown here that telmisartan suppressed the proliferation of the cultured human gastric cancer cell lines MKN74, MKN1 and MKN45 as detected in the CCK‑8 assay. In a mouse xenograft model of gastric cancer, telmisartan suppressed tumor growth by arresting the cell cycle at the G0/G1phase through inhibition of the expression of cyclinD1, the catalytic subunit of cyclin dependent kinase4 (CDK4), as well as the phosphorylation of the tumor suppressor retinoblastoma (pRb) protein as detected by western blotting. Notably, telmisartan did not induce apoptosis, as indicated by consistent levels of caspase‑cleaved keratin18 in MKN74cells. Furthermore, telmisartan inhibited the phosphorylation of epidermal growth factor receptor (EGFR) and increased the levels of the angiogenesis‑related protein tissue inhibitor of metalloproteinase‑1 (TIMP‑1). Analyses of microarrays revealed that telmisartan altered the expression of miRNAs in MKN74cells. In conclusion, telmisartan suppressed the proliferation of human gastric cancer cells by inducing cell cycle arrest.