Advances of the regulatory mechanism of cyclin, cyclin- dependent kinases and related kinase inhibitors in cell cycle progression / 生物工程学报

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 kinase 8 and its inhibitors in antitumor therapy: research advances / 国际药学研究杂志

Cyclin-dependent kinase 8(CDK8)regulates transcription by binding to mediator complex or phosphorylating transcriptional factors. Recent studies have reported that overexpressed CDK8 leads to the development of colorectal cancer, breast cancer and hematological malignancies by activating Wnt- β- catenin, promoting the transcription of estrogen- inducible genes and inhibiting the expression of super enhancer-associated genes. These studies have indicated that CDK8 is a potential antitumor target. This paper briefly discusses the biological function of CDK8 and the regulatory mechanism of CDK8 on the tumorigenesis and its development, and reviews on the research progress in CDK8 inhibitors, hoping to provide a reference CDK8-targeting cancer therapy.

Effect of high expression of Zwint on the proliferation of hepatoma cells and the prognosis of liver transplantation for hepatocellular carcinoma / 器官移植

Objective To investigate the expression of zeste white 10 interactor (Zwint) in primary hepatocellular carcinoma (HCC) and its effect on the prognosis of liver transplantation for HCC. Methods HCC tissues, paracancerous tissues and clinical data of 50 liver transplant recipients for HCC were collected. The expression levels of Zwint messenger RNA (mRNA) and Zwint protein in 20 pairs of HCC tissues and paracancerous tissues of 20 liver transplant recipients for HCC were compared using real-time fluorescence quantitative polymerase chain reaction (PCR), Western Blot and immunohistochemistry (IHC). Two HCC cell lines HepG-2 which interfered with the expression of Zwint successfully were selected as si-Zwint-1 group and si-Zwint-2 group, and the blank control was taken as si-NC group. The cell proliferation and cell cycle of various groups were compared using cell counting kit (CCK) -8 experiment, flat-cloning assay and cell cycle experiment. The consistency of the expression of Zwint and cyclin D1 in HCC tissues and cells was analyzed using Western Blot and IHC. The enrolled patients were divided into high expression group (22 cases) and low expression group (28 cases) based on the median of Zwint protein expression level, and the relationship of the expression level of Zwint protein and clinical characteristics, overall survival rate and disease free survival rate of liver transplant recipients for HCC was analyzed. Results The results of real-time fluorescence quantitative PCR showed that the expression level of Zwint mRNA in HCC tissues was higher than that of paracancerous tissues (P=0.03). The results of Western Blot and IHC showed that the expression level of Zwint protein in HCC tissues was higher than that of paracancerous tissues(both P<0.05).After the Zwint gene of HCC cell line HepG-2 was interfered,CCK-8 and flat-cloning assay showed that the cell proliferation potential was significantly weakened (all P<0.01), and the cell cycle arrested at stage G1(all P<0.05). The expression level of Zwint protein was closely related to tumor diameter and tumor, node, metastasis (TNM) staging (all P<0.05). The overall survival rate of liver transplant recipients for HCC in the high Zwint expression group was lower than that of the low expression group (P=0.02). Conclusions Zwint is highly expressed in HCC tissues, and it can promote the proliferation of HCC cells through regulating cell cycle. The expression level of Zwint is negatively correlated with the prognosis of liver transplantation for HCC.

Dysregulation of Cell Cycle Regulating Proteins in Peripheral Lymphocytes from the Patients with Alzheimer's Disease / 대한정신약물학회지

OBJECTIVE: Extensive neuronal death occurring in the Alzheimer's disease (AD) may be related with the apoptosis. Recent studies have suggested that regulatory failure of cell cycle appeared to be very early event of AD pathogenesis in neuronal cells as well as in peripheral lymphocytes. We compared the change of cyclin dependent kinases (Cdks), which is related with G1/S phase transition in the cell cycle, between AD patients and normal controls using peripheral lymphocytes. METHODS: We obtained Cdks from peripheral lymphocytes of 37 AD patients and 18 age-matched normal subjects. Cells in first culture were considered to be G-zero (G0) cells. We measured Cdk2, Cdk4, and Cdk6 at baseline (T0). Thereafter, we observed Cdks 24 hours later after using PHA (phytohemaglutinin) (N24). Meanwhile, we observed Cdks 24 hours later again with rapamycin treatment (T24). RESULTS: At baseline (T0), Cdk2 and Cdk6 were increased in AD patients compared to the control group (p< 0.001, p=0.038, respectively). Cdk2 was increased in AD patients more than control group after using PHA (T24, p=0.007). After rapamycin treatment for 24 hours (N24), Cdk2, Cdk4, and Cdk6 were increased in the patients compared to the controls (p=0.002, p=0.022, p=0.011, respectively). CONCLUSION: This results showed that the cell cycle regulating proteins in AD patients, which are related with G1/S phase transition, were increased in peripheral lymphocytes compared to those in normal controls. We provide the clue which demonstrate the cell cycle dysregulation in the patients with Alzheimer's disease.

Expression of Cyclin Dependent Kinase (CDK) Inhibitors in Cervical Carcinoma / 대한부인종양콜포스코피학회잡지

Recent studies have revealed a new family of tumor suppressor genes that directly implicate aberrant cell cycle regulation in tumorigenesis. The general function of these gene products is that they prevent cell cycle progression by directly interfering with cyclin/cyclin dependent kinase (CDK) activation. The importance of these genes is that they are potent inhibitors of CDK and are induced by p53. Among these cell cycle inhibitors, p21WAF1/CIP1 and p16 have been thoroughly studied. However, the role of p21WAF1/CIP1 and p16 in tumorigenesis of the uterine cervix has been poorly defined. We used immunohistochemical techniques to study the expression of these cell cycle inhibitors in formalin-fixed, paraffin-embedded cervical tissue to explore the relationship between cyclin/CDK inhibitors and cervical carcinoma. Cervical tissues were analyzed from 46 patients with cervical carcinoma, 30 cases with cervical intraepithelial neoplasia (CIN) and 22 control cases who underwent hysterectomy due to benign gynecologic disease at Yonsei University College of Medicine. All CDK inhibitors strongly expressed in the reverse cell hyperplasia and koilocytes, whereas they revealed significantly decreased expression in neoplastic tissues (p<0.05). Normal endocervical cells revealed focal and weak expression to all CDK inhibitors but p16 showed no expression in endocervical adenocarcinoma. P16 revealed higher expressions in cases associated with human papilloma virus (HPV) (t-test, p<0.05) than in cases lacking any type of HPV. Our results were consistent with the concept that underexpression of CDK inhibitors may play an important role in neoplastic transformation in cervical carcinoma.