Cell cycle plays a crucial role in cell development. Cell cycle progression is mainly regulated by cyclin dependent kinase (CDK), cyclin and endogenous CDK inhibitor (CKI). Among these, CDK is the main cell cycle regulator, binding to cyclin to form the cyclin-CDK complex, which phosphorylates hundreds of substrates and regulates interphase and mitotic progression. Abnormal activity of various cell cycle proteins can cause uncontrolled proliferation of cancer cells, which leads to cancer development. Therefore, understanding the changes in CDK activity, cyclin-CDK assembly and the role of CDK inhibitors will help to understand the underlying regulatory processes in cell cycle progression, as well as provide a basis for the treatment of cancer and disease and the development of CDK inhibitor-based therapeutic agents. This review focuses on the key events of CDK activation or inactivation, and summarizes the regulatory processes of cyclin-CDK at specific times and locations, as well as the progress of research on relevant CDK inhibitor therapeutics in cancer and disease. The review concludes with a brief description of the current challenges of the cell cycle process, with the aim to provide scientific references and new ideas for further research on cell cycle process.
Cyclin-Dependent Kinases/metabolism* ; Cyclins/metabolism* ; Protein Serine-Threonine Kinases ; Cell Cycle Proteins/metabolism* ; Cell Cycle/physiology* ; Cyclin-Dependent Kinase 2

The cell cycle is a complex process that involves DNA replication, protein expression, and cell division. Dysregulation of the cell cycle is associated with various diseases. Cyclin-dependent kinases (CDKs) and their corresponding cyclins are major proteins that regulate the cell cycle. In contrast to inhibition, a new approach called proteolysis-targeting chimeras (PROTACs) and molecular glues can eliminate both enzymatic and scaffold functions of CDKs and cyclins, achieving targeted degradation. The field of PROTACs and molecular glues has developed rapidly in recent years. In this article, we aim to summarize the latest developments of CDKs and cyclin protein degraders. The selectivity, application, validation and the current state of each CDK degrader will be overviewed. Additionally, possible methods are discussed for the development of degraders for CDK members that still lack them. Overall, this article provides a comprehensive summary of the latest advancements in CDK and cyclin protein degraders, which will be helpful for researchers working on this topic.
Humans ; Cell Cycle/physiology* ; Cell Division ; Cyclin-Dependent Kinases/metabolism* ; Cyclins/metabolism*

OBJECTIVETo explore the role of F10 gene in regulating cell cycles of choriocarcinoma cells and the underlying mechanisms.

METHODSUsing untreated cells as the control, JAR cells with F10 gene silencing or stable F10 over-expression were examined for cell cycle changes by flow cytometry (FCM) and for expressions of cyclin and cyclin-dependent kinase (CDKs) with Western blotting and immunofluorescence technique.

RESULTSJAR cells over-expressing F10 gene showed reduced duration of cell cycle compared with untreated and with cells after F10 gene silencing. In F10-over-expressing cells, Western blotting revealed significantly up-regulated expressions of cyclin A2, B1, D1, E and CDK2, 6, and 7, but not CDK4, as compared with the control cells and cells with F10 gene silencing (P<0.05), and these results were consistent with those by immunofluorescence assay.

CONCLUSIONF10 gene may accelerate cell cycle progression and promote cell proliferation by up-regulating the expressions of cyclin A2, B1, D1, E and CDK 2, 4, 6, 7 in choriocarcinoma cells.

Cell Cycle ; Cell Division ; Cell Line, Tumor ; Cell Proliferation ; Choriocarcinoma ; metabolism ; Cyclin-Dependent Kinases ; metabolism ; Cyclins ; metabolism ; Factor X ; genetics ; Female ; Gene Silencing ; Humans ; Pregnancy

OBJECTIVETo investigate the effect of solanine on the growth of human prostate cancer cell xenograft in nude mice.

METHODSHuman prostate cancer Du145 cells were injected into the subcutaneous layers on the back of nude mice. After a week, the mice bearing subcutaneous tumor graft were randomly divided into solanine treatment group and saline control group for treatment for 3 weeks. The tumor grafts were then harvested to evaluate the inhibition rate. The mRNA and protein expressions of cell cycle-related genes in the tumors were detected by qRT-PCR and Western blotting, respectively, and tumor cell apoptosis was detected using TUNEL method.

RESULTSThe tumor growth rate in solanine-treated group was significantly slower than that in the control group (P<0.01). The mRNA and protein expressions of C-myc, cyclin D1, cyclin E1, CDK2, CDK4 and CDK6 were significantly inhibited by solanine. Solanine significantly up-regulated p21 mRNA and protein expression in the tumors and induced a higher apoptosis rate of the tumor cells than saline (P<0.01).

CONCLUSIONThe tumor-inhibition effect of solanine is probably mediated by regulating the expressions of genes related with G1/S cell cycle arrest and cell apoptosis.

Animals ; Apoptosis ; Cyclin-Dependent Kinases ; metabolism ; Cyclins ; metabolism ; G1 Phase Cell Cycle Checkpoints ; Humans ; Male ; Mice ; Mice, Nude ; Neoplasm Transplantation ; pathology ; Prostatic Neoplasms ; drug therapy ; pathology ; S Phase ; Solanine ; pharmacology

Meiotic recombination is carried out through a specialized pathway for the formation and repair of DNA double-strand breaks (DSBs) made by the Spo11 protein. The present study shed light on the functional role of cyclin, CYC2, in Tetrahymena thermophila which has transcriptionally high expression level during meiosis process. Knocking out the CYC2 gene results in arrest of meiotic conjugation process at 2.5-3.5 h after conjugation initiation, before the meiosis division starts, and in company with the absence of DSBs. To investigate the underlying mechanism of this phenomenon, a complete transcriptome profile was performed between wild-type strain and CYC2 knock-out strain. Functional analysis of RNA-Seq results identifies related differentially expressed genes (DEGs) including SPO11 and these DEGs are enriched in DNA repair/mismatch repair (MMR) terms in homologous recombination (HR), which indicates that CYC2 could play a crucial role in meiosis by regulating SPO11 and participating in HR.
Cell Cycle Checkpoints ; Cyclins ; genetics ; metabolism ; DNA Breaks, Double-Stranded ; DNA Mismatch Repair ; DNA Repair ; Endodeoxyribonucleases ; genetics ; metabolism ; Homologous Recombination ; Meiosis ; Microscopy, Fluorescence ; Phenotype ; Protozoan Proteins ; genetics ; metabolism ; Real-Time Polymerase Chain Reaction ; Sequence Analysis, RNA ; Tetrahymena thermophila ; genetics ; metabolism ; Transcriptome

Neural stem cells (NSCs) proliferation can be influenced by repetitive transcranial magnetic stimulation (rTMS) in vivo via microRNA-106b-25 cluster, but the underlying mechanisms are poorly understood. This study investigated the involvement of microRNA-106b-25 cluster in the proliferation of NSCs after repetitive magnetic stimulation (rMS) in vitro. NSCs were stimulated by rMS (200/400/600/800/1000 pulses per day, with 10 Hz frequency and 50% maximum machine output) over a 3-day period. NSCs proliferation was detected by using ki-67 and EdU staining. Ki-67, p21, p57, cyclinD1, cyclinE, cyclinA, cdk2, cdk4 proteins and miR-106b, miR-93, miR-25 mRNAs were detected by Western blotting and qRT-PCR, respectively. The results showed that rMS could promote NSCs proliferation in a dose-dependent manner. The proportions of ki-67+ and Edu+ cells in 1000 pulses group were 20.65% and 4.00%, respectively, significantly higher than those in control group (9.25%, 2.05%). The expression levels of miR-106b and miR-93 were significantly upregulated in 600-1000 pulses groups compared with control group (P<0.05 or 0.01 for all). The expression levels of p21 protein were decreased significantly in 800/1000 pulses groups, and those of cyclinD1, cyclinA, cyclinE, cdk2 and cdk4 were obviously increased after rMS as compared with control group (P<0.05 or 0.01 for all). In conclusion, our findings suggested that rMS enhances the NSCs proliferation in vitro in a dose-dependent manner and miR-106b/p21/cdks/cyclins pathway was involved in the process.
Animals ; Animals, Newborn ; Biomarkers ; metabolism ; Cell Proliferation ; genetics ; Cyclin-Dependent Kinase 2 ; genetics ; metabolism ; Cyclin-Dependent Kinase 4 ; genetics ; metabolism ; Cyclin-Dependent Kinase Inhibitor p21 ; genetics ; metabolism ; Cyclin-Dependent Kinase Inhibitor p57 ; genetics ; metabolism ; Cyclins ; genetics ; metabolism ; Gene Expression Regulation ; Hippocampus ; cytology ; metabolism ; Ki-67 Antigen ; genetics ; metabolism ; Magnetic Fields ; MicroRNAs ; genetics ; metabolism ; Neural Stem Cells ; cytology ; metabolism ; Primary Cell Culture ; Rats ; Rats, Sprague-Dawley ; Signal Transduction

Although it has been suggested that kinesin family member 14 (KIF14) has oncogenic potential in various cancers, including hepatocellular carcinoma (HCC), the molecular mechanism of this potential remains unknown. We aimed to elucidate the role of KIF14 in hepatocarcinogenesis by knocking down KIF14 in HCC cells that overexpressed KIF14. After KIF14 knockdown, changes in tumor cell growth, cell cycle and cytokinesis were examined. We also examined cell cycle regulatory molecules and upstream Skp1/Cul1/F-box (SCF) complex molecules. Knockdown of KIF14 resulted in suppression of cell proliferation and failure of cytokinesis, whereas KIF14 overexpression increased cell proliferation. In KIF14-silenced cells, the levels of cyclins E1, D1 and B1 were profoundly decreased compared with control cells. Of the cyclin-dependent kinase inhibitors, the p27Kip1 protein level specifically increased after KIF14 knockdown. The increase in p27Kip1 was not due to elevation of its mRNA level, but was due to inhibition of the proteasome-dependent degradation pathway. To explore the pathway upstream of this event, we measured the levels of SCF complex molecules, including Skp1, Skp2, Cul1, Roc1 and Cks1. The levels of Skp2 and its cofactor Cks1 decreased in the KIF14 knockdown cells where p27Kip1 accumulated. Overexpression of Skp2 in the KIF14 knockdown cells attenuated the failure of cytokinesis. On the basis of these results, we postulate that KIF14 knockdown downregulates the expression of Skp2 and Cks1, which target p27Kip1 for degradation by the 26S proteasome, leading to accumulation of p27Kip1. The downregulation of Skp2 and Cks1 also resulted in cytokinesis failure, which may inhibit tumor growth. To the best of our knowledge, this is the first report that has identified the molecular target and oncogenic effect of KIF14 in HCC.
Carcinoma, Hepatocellular/*metabolism ; Cyclin-Dependent Kinase Inhibitor p27/genetics/*metabolism ; Cyclins/genetics/metabolism ; *Cytokinesis ; Gene Silencing ; Hep G2 Cells ; Humans ; Kinesin/genetics/*metabolism ; Liver Neoplasms/*metabolism ; Oncogene Proteins/genetics/*metabolism ; Proteasome Endopeptidase Complex/metabolism ; RNA, Messenger/genetics/metabolism ; S-Phase Kinase-Associated Proteins/genetics/metabolism ; *Ubiquitination

OBJECTIVETo characterize the human primary cyclins (D1, E, A, B1) expressed in gastric carcinoma, and to clarify the relationship between the types of expressed primary cyclins and clinicopathological features of gastric carcinoma.

METHODSPrimary cyclins (D1, E, A, B1) expressed in single cells separated from 68 cases gastric carcinoma tissues were analyzed by flow cytometry. We classified the gastric carcinomas by different types of the expressed primary cyclins, and explore the roles of primary cyclins expressed in cell cycle and the expression patterns of the cyclins. The results were analyzed together with clinicopathological features.

RESULTSThe patterns of expressed primary cyclins could be classified into five types. The proportion was 10.3% (7/68), 22.1% (15/68), 25.0% (17/68), 29.4% (20/68), and 13.2% (9/68), respectively, from type I to type V. Each type could be, according to the degree of in-cycle cyclins expressed, divided into different sub-types. The types of primary cyclins expressed were strongly linked to invasive depth and lymph node metastasis of the gastric carcinoma (P < 0.01). The rates of lymph node metastasis were 26.6%, 43.8%, 82.3%, 95.0%, and 100.0%, respectively, from type I to type V. The type of primary cyclins expressed was also significantly associated with disease stage (TNM stage). The proportion of stage IV disease was 0, 6.7%, 17.6%, 25.0% and 55.6%, respectively, from type I to type V. It was shown that there were relationships between the sub-types of primary cyclins expressed and different growth-types, degree of cell differentiation, or, the tumor gross types (P < 0.01).

CONCLUSIONSThe types of primary cyclins expression are different in the process of the occurrence, development and metastasis of gastric carcinoma, and are correlated with clinicopathological features of gastric carcinoma.

Adult ; Aged ; Aged, 80 and over ; Cell Differentiation ; Cyclin A1 ; metabolism ; Cyclin B1 ; metabolism ; Cyclin D1 ; metabolism ; Cyclin E ; metabolism ; Cyclins ; classification ; metabolism ; Female ; Humans ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Invasiveness ; Neoplasm Staging ; Oncogene Proteins ; metabolism ; Stomach Neoplasms ; metabolism ; pathology

This study investigated the potential role of ERK1/2-cyclinE1 signaling pathway in rat pulmonary artery smooth muscle cells (rPASMCs) proliferation and pulmonary vascular remodeling induced by cigarette smoke exposure. A total of 24 male Wistar rats were randomly divided into 4 groups: control group (C group), S-1M, S-3M and S-6M groups (animals in the groups were exposed to smoke for 1, 3, and 6 months, respectively). HE staining and anti-α-smooth muscle actin antibody staining were performed to observe the degree of pulmonary vascular remodeling. Immunohistochemistry and Western blotting were performed to evaluate ERK1/2 and cyclinE1 expression in pulmonary vessels. Primary cultured rat pulmonary artery smooth muscle cells (rPASMCs) were exposed to cigarette smoke extract (CSE). ERK inhibitor (PD98059) and cyclinE1 siRNA were used to verify the role of ERK1/2 and cyclinE1 in CSE-induced rPASMCs proliferation. Cell proliferation was assessed by cell counting and 5-bromo-2-deoxyuridine (BrdU) incorporation. Our results showed that abnormal pulmonary vascular remodeling was found in cigarette smoked rats. Compared to C group, activated ERK1/2 and cyclinE1 expression was significantly increased in smoke-exposure groups. This up-regulated expression was positively correlated with the severity of pulmonary vascular remodeling, and there was positive correlation between the expression of ERK1/2 and cyclinE1. PD98059 and cyclinE1 siRNA inhibited the proliferation of rPASMCs. The expression of cyclinE1 could be down-regulated by PD98059. Our data demonstrated that increased expression of ERK1/2 and cyclinE1 might be involved in the pathogenesis of abnormal rPASMCs proliferation and rat pulmonary vascular remodelling induced by cigarette smoke exposure.
Animals ; Cells, Cultured ; Cyclins ; metabolism ; MAP Kinase Signaling System ; Male ; Myocytes, Smooth Muscle ; metabolism ; pathology ; Pulmonary Artery ; metabolism ; pathology ; Rats ; Rats, Wistar ; Smoking ; metabolism ; pathology ; Up-Regulation

OBJECTIVETo study the expression of A-kinase anchor protein 95 (AKAP95), cyclin E(2), and connexin 43 (Cx43) in lung cancer tissue, the clinical significance of their expression, and the expression correlation among the three proteins.

METHODSFifty-one samples of lung cancer tissue were examined by immunohistochemistry to measure the expression of AKAP95, cyclin E2, and Cx43.

RESULTSThe positive rate of AKAP95 expression in lung cancer tissue was significantly higher than that in paracancerous tissue (82.35% vs 33.33%, P < 0.05); AKAP95 expression was associated with the cell differentiation and histopathological type of lung cancer (P < 0.05). The positive rate of cyclin E(2) expression in lung cancer tissue was significantly higher than that in paracancerous tissue (43.14% vs 13.33%, P < 0.05); cyclin E(2) expression was associated with the lymph node metastasis and histopathological type of lung cancer (P < 0.05). The positive rate of Cx43 expression in lung cancer tissue was lower than that in paracancerous tissue (60.78% vs 80.00%); Cx43 expression was associated with the cell differentiation, lymph node metastasis, and histopathological type of lung cancer (P < 0.05). There was correlation between each two of AKAP95 expression, cyclin E(2) expression, and Cx43 expression in lung cancer tissue.

CONCLUSIONHigh expression of AKAP95 and cyclin E(2) plays an important role in the occurrence and development of lung cancer. AKAP95 expression is associated with the cell differentiation and histopathological type of lung cancer, and cyclin E2 expression is associated with lymph node metastasis and histopathological type. There is correlation between each two of AKAP95 expression, cyclin E(2) expression, and Cx43 expression in lung cancer tissue.

A Kinase Anchor Proteins ; metabolism ; Adult ; Aged ; Connexin 43 ; metabolism ; Cyclins ; metabolism ; Female ; Humans ; Lung ; metabolism ; pathology ; Lung Neoplasms ; metabolism ; pathology ; Lymphatic Metastasis ; Male ; Middle Aged