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1.
Acta Pharmaceutica Sinica B ; (6): 309-321, 2021.
Article in English | WPRIM | ID: wpr-881138

ABSTRACT

Cullin-RING ligases (CRLs) recognize and interact with substrates for ubiquitination and degradation, and can be targeted for disease treatment when the abnormal expression of substrates involves pathologic processes. Phosphorylation, either of substrates or receptors of CRLs, can alter their interaction. Phosphorylation-dependent ubiquitination and proteasome degradation influence various cellular processes and can contribute to the occurrence of various diseases, most often tumorigenesis. These processes have the potential to be used for tumor intervention through the regulation of the activities of related kinases, along with the regulation of the stability of specific oncoproteins and tumor suppressors. This review describes the mechanisms and biological functions of crosstalk between phosphorylation and ubiquitination, and most importantly its influence on tumorigenesis, to provide new directions and strategies for tumor therapy.

2.
Article in Chinese | WPRIM | ID: wpr-805293

ABSTRACT

Objective@#To investigate the expression and clinical significance of ribonucleotide reductase small subunit M2 (RRM2) in chronic hepatitis B virus (HBV) infection and related liver diseases.@*Methods@#A total of 428 patients with chronic HBV infection and liver disease were enrolled from Songyang County People’s Hospital from October 2017 to September 2019. There were 166 cases of chronic hepatitis B (CHB), 53 cases of HBV-related cirrhosis, 28 cases of non-HBV-related cirrhosis, 57 cases of HBV-related liver cancer, 33 cases of non-HBV-related liver cancer, and 91 cases of non-viral hepatitis. In addition, 36 healthy subjects were selected as the control group. Among 166 cases of CHB, there were 87 patients with high viral load group (HBV DNA ≥4.0 lg IU/mL) and 79 patients with low viral load group (HBV DNA <4.0 lg IU/mL); while in 87 high viral load patients, 56 had high alanine transaminase (ALT) (≥40 U/L) and 31 had normal ALT (<40 U/L). The expression level of serum RRM2 protein in patients was detected by enzyme-linked immunosorbent assay (ELISA), and the relationship of RRM2 expression with HBV DNA and liver function was analyzed. SPSS 23.0 and PRISM 8.0 statistical software were used to analyze data. Correlation analysis was performed using Spearman analysis.@*Results@#The serum ALT and RRM2 levels in patients with high viral load CHB were higher than those in low viral load group (Z=-6.68, t=6.80, P<0.01). Patients with HBV-related cirrhosis had higher serum RRM2 levels than those with non-HBV-related cirrhosis (t=9.16, P<0.01). The serum RRM2 level was higher in patients with HBV-related liver cancer than that in patients with non-HBV-related liver cancer (t=12.42, P<0.01). Among patients with high viral load CHB, there was no significant difference in serum RRM2 levels between patients with ALT ≥40 U/L group and patients with ALT <40 U/L group (t=0.51, P>0.05). The level of ALT in the non-viral hepatitis group was higher than that in the healthy control group (Z=-8.43, P<0.01), but there was no significant difference in serum RRM2 levels between the two groups (t=1.03, P>0.05). Correlation analysis showed that serum RRM2 level was positively correlated with HBV DNA load (r=0.51, P<0.01), but not correlated with liver function indicators such as ALT and aspartate aminotransferase (all P>0.05) in patients with chronic HBV infection and related liver diseases.@*Conclusions@#Serum RRM2 level is positively correlated with HBV DNA load and has no significant correlation with ALT. RRM2 might be used as a target for the development of new hepatitis B drugs.

3.
Article in Chinese | WPRIM | ID: wpr-772069

ABSTRACT

OBJECTIVE@#To investigate the effects of ribonucleotide reductase catalytic subunit M1 (RRM1) gene silencing on drug resistance of human breast cancer cell line MCF-7/R.@*METHODS@#We established a paclitaxel-resistant breast cancer MCF-7 cell line (MCF-7/R) by exposing the cells to high-concentration paclitaxel in a short time. Small interfering RNAs (siRNAs) targeting RRM1 were designed to silence RRM1 expression in human breast cancer MCF-7/R cells. MTT assay was used to detect the IC values and the sensitivity to paclitaxel in the cells with or without siRNA transfection. The changes in the proliferative activity of MCF7 and MCF-7/R cells following RRM1 gene silencing were evaluated using EdU assay. Flow cytometry was used to analyze the cell apoptosis and cell cycle changes. We assessed the effect of RRM1 gene silencing and paclitaxel on the tumor growth in a nude mouse model bearing subcutaneous xenografts with or without siRNA transfection.@*RESULTS@#We detected significantly higher expressions of RRM1 at both the mRNA and protein levels in the drug-resistant MCF- 7/R cells than in the parental MCF-7 cells ( < 0.01). Transfection with the specific siRNAs significantly reduced the expression of RRM1 in MCF-7/R cells ( < 0.05), which showed a significantly lower IC value of paclitaxel than the cells transfected with the negative control siRNA ( < 0.05). RRM1 silencing significantly inhibited the proliferation ( < 0.01) and enhanced the apoptosis-inducing effect of paclitaxel in MCF-7/R cells ( < 0.001); RRM1 silencing also resulted in obviously reduced Akt phosphorylation, suppressed Bcl-2 expression and promoted the expression of p53 protein in MCF-7/R cells. In the tumor-bearing nude mice, the volume of subcutaneously transplanted tumors was significantly smaller in MCF-7/R/siRNA+ PTX group than in the other groups ( < 0.001).@*CONCLUSIONS@#RRM1 gene silencing can reverse paclitaxel resistance in human breast cancer cell line MCF-7/R by promoting cell apoptosis.


Subject(s)
Animals , Apoptosis , Breast Neoplasms , Drug Resistance, Neoplasm , Gene Silencing , Humans , MCF-7 Cells , Mice , Mice, Nude , Paclitaxel , RNA, Small Interfering , Ribonucleotide Reductases , Tumor Suppressor Proteins
4.
China Pharmacy ; (12): 4897-4901, 2017.
Article in Chinese | WPRIM | ID: wpr-664478

ABSTRACT

OBJECTIVE:To investigate the correlation between ribonucleotide reductase M1 subunit (RRM1) single nucleo-tide polymorphisms (SNPs) and chemotherapy sensitivity of patients with non-small cell lung cancer (NSCLC) for gemcitabine. METHODS:A total of 96 NSCLC patients receiving primary treatment selected from our hospital during Aug. 2014-Jul. 2016 were all accepted gemcitabine-based two-drug chemotherapy plan,with continuous treatment for at least 2 cycles(28 d as a cycle). Che-motherapy sensitivity rate was calculated by using the ratio of the sum of patients with complete response and partial response to the sum of test patients. RRM1 genotype was tested by PCR and direct sequencing. The correlation between different genotypes and chemotherapy sensitivity was analyzed. RESULTS:Distribution frequency of RRM1-37C>A CC, CA, AA genotype were 35.42%,52.08%,12.50%,respectively;distribution frequency of-524C>T CC,CT,TT genotype were 18.75%,37.50%, 43.75%,respectively. The frequency of each genotype was in the line with Hardy-Weinberg equilibrium(P>0.05). Chemotherapy sensitivity rate of 96 NSCLC patients was 37.50%. The patient's age,sex,ethnicity,smoking or not,TNM stage,pathological type,chemotherapy plan,and the Eastern American Oncology Collaboration score were not associated with chemotherapy sensitivi-ty (P>0.05). Chemotherapy sensitivity rates of RRM1(-37CA)+(-524CT)genotype and (-37CC)+(-524TT) genotype patients (57.14%,39.39%) were significantly higher than those of other genotype patients (10.71%),with statistical significance (P<0.05). There was no statistical significance in chemotherapy sensitivity rate between RRM1(-37CA)+(-524CT) and (-37CC)+(-524TT)genotype patients. CONCLUSIONS:In NSCLC patients,the SNPs of RRM1 can be used as predictive factor for the sen-sitivity of gemcitabine chemotherapy,and RRM1(-37CA)+(-524CT)and(-37CC)+(-524TT)genotype patients have higher sensi-tivity to this type of chemotherapy.

5.
Article in English | WPRIM | ID: wpr-195565

ABSTRACT

Deoxyribonucleotides (dNTPs) are important for the efficient growth of DNA viruses. Therefore, many DNA viruses have strategies for the upregulation of cellular dNTP levels. Both α- and γ-herpesviruses encode functional homologs of cellular dNTP anabolic enzymes, including the class I ribonucleotide reductase (RNR) large (R1) and small (R2) subunits, whereas β-herpesviruses modulate host cells to induce genes that increase dNTP levels. Interestingly, β-herpesviruses still express the nonfunctional RNR R1 subunit. However, it is not clear why β-herpesviruses still carry inactive R1 homologs. Recently, the R1 homologs of herpesviruses have been shown to inhibit innate immune signaling pathways. In particular, both functional and nonfunctional R1 homologs target receptor-interacting protein kinase 1 (RIP1) and inhibit RIP1-mediated signaling pathways to promote viral replication. Here, we summarize recent findings on the activity of herpesviral R1 homologs and discuss their roles in the regulation of innate immune signaling pathways.


Subject(s)
Deoxyribonucleotides , DNA Viruses , Herpesviridae , Protein Kinases , Ribonucleotide Reductases , Up-Regulation
6.
Cancer Research and Clinic ; (6): 447-451, 2016.
Article in Chinese | WPRIM | ID: wpr-495434

ABSTRACT

Objective To investigate the significance of resistant gene detection combined with adenosine triphosphate-tumor chemosensitivity assay (ATP-TCA) in the second-line chemotherapy of lung squamous cell cancer, and to provide a reference for clinical treatment. Methods 150 patients with lung squamous cell cancer diagnosed by histopathology or cytology and with the disease progressed after NP regime chemotherapy were enrolled. The mRNA expressions of excision repair cross complementation 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) were detected by RT-PCR, and ATP-TCA was carried out. After detected by RT-PCR and ATP-TCA, the patients who were sensitive to gemcitabine plus cisplatin (GP) accepted the second-line systemic chemotherapy with GP regimen, and the others who were not sensitive to GP regimen or whose results of gene detection and ATP-TCA were on the contrary took the second-line chemotherapy regimens with docetaxel plus cisplatin (DP). Both groups accepted 2-4 cycles of systemic chemotherapy. The chest CT was followed up, and the response rate (RR), progression-free survival (PFS) and median survival time (MST) were investigated. Results The RR of GP group was 36.2 % (17/47), while the DP group was 28.1 % (26/92), and the difference was statistically significant (χ2= 4.274, P 0.05). Conclusion The resistance gene detection combined with ATP-TCA have certain guiding significance on the second-line chemotherapy for advanced lung squamous cell cancer.

7.
Article in Chinese | WPRIM | ID: wpr-489640

ABSTRACT

Objective To investigate the expression of human ribonucleotide reductase large subunit M1 (RRM1) in the patients with gastric adenocarcinoma and its clinical significance.Methods The expressions of RRM1 were detected in 88 cases of gastric adenocarcinoma and 20 cases of nonnal gastric tissues by immunohistochemical method.The correlations between the expression of RRM1 and clinicopathological characteristics were analyzed.Results The positive expression rate of RRM1 in gastric adenocarcinoma was 83.0%(73/88).And RRM1 was negative in the entire normal gastric tissues.The positive expression of RRM1 was not associated with patient's age (x2 =0.352,P=0.553),gender (x2 =0.493,P=0.482),depth of tumor infiltration depth (x2 =0.007,P =0.933),lymph nodes metastasis (x2 =0.121,P =0.728) and distant metastasis (P =0.415).But it was related to the degree of tumor differentiation (x2 =7.740,P =0.021) and clinical stage (x2 =5.733,P =0.017).Conclusion The expression of RRM1 is positive expression in most gastric adenocarcinoma,and is associated with the degree of tumor differentiation and clinical stage.It is of great significance to detect the expression of RRM1 in gastric adenocarcinoma for confirming the diagnosis and judging malignant degree of the tumor.It also may have potential value in choosing the best therapeutic scheme and estimating prognosis.

8.
China Pharmacy ; (12): 4792-4794, 2015.
Article in Chinese | WPRIM | ID: wpr-501213

ABSTRACT

OBJECTIVE:To study the correlation between RRM2 expression of cervical cancer cell line C33a and Siha and cell sensitivity to gemcitabine(Gem). METHODS:C33a and Siha were treated with 0.1-3.2 μmol/L and 0.5-512 μmol/L of gemcitabine respectively for 72 h;cell viability was measured by MTT assay to calculate the value of IC50. The expression of RRM2 was mea-sured by Western blot and RT-PCR. Siha cell was treated with gradient concentration and large dose of Gem to establish Siha/Gem drug-resistant cell line. RNA interference technology knockdown the expression of RRM2 in Siha/Gem cell,and IC50 of Gem to cell was determined before and after knockdown. RESULTS:The IC50 values of Gem to Siha and C33a were 16.8 μmol/L and 0.63μmol/L. Compared with C33a cells,the expression of RRM2 in Siha cell was higher. Compared with Siha cells,Siha/Gem drug-re-sistant cell(drug resistant index of 16.26)showed higher RRM2 expression. Siha/Gem drug-resistant cell knockdown RRM2,IC50 of Gem to it was decreased,and inverse drug resistant times was 4.24. CONCLUSIONS:There is an negative correlation between RRM2 expression and Gem sensitivity in cervical cancer cell lines. The knockdown of RRM2 in Siha/Gem increases the sensitivity to Gem.

9.
Gut and Liver ; : 662-668, 2014.
Article in English | WPRIM | ID: wpr-37648

ABSTRACT

BACKGROUND/AIMS: Ribonucleotide reductase subunit M2 (RRM2) catalyzes the production of deoxynucleotide triphosphates, which are necessary for DNA synthesis. RRM2 has been reported to play an active role in tumor progression, and elevated RRM2 levels have been correlated with poor prognosis for colorectal cancer patients. This study aimed to elucidate the prognostic significance of RRM2 protein expression in hepatocellular carcinoma after surgery. METHODS: RRM2 protein expression was evaluated using immunohistochemistry in tumor tissues from 259 hepatocellular carcinoma patients who underwent curative hepatectomy. RESULTS: High RRM2 expression was observed in 210 of 259 patients (81.1%) with hepatocellular carcinomas. High RRM2 expression was significantly associated with viral etiology (p=0.035) and liver cirrhosis (p=0.036). High RRM2 expression was correlated with early recurrence (p=0.004) but not with late recurrence (p=0.144). Logistic regression analysis revealed that high RRM2 expression (p=0.040) and intrahepatic metastasis (p<0.001) were independent predictors of early recurrence. High RRM2 expression unfavorably influenced both shorter recurrence-free survival (p=0.011) and shorter disease-specific survival (p=0.002) and was an independent predictor of shorter disease-specific survival (p=0.008). CONCLUSIONS: High RRM2 protein expression might be a useful marker for predicting early recurrence and may be a marker for poor prognosis of hepatocellular carcinoma after curative hepatectomy.


Subject(s)
Adolescent , Adult , Aged , Carcinoma, Hepatocellular/metabolism , Disease-Free Survival , Female , Hepatectomy , Humans , Immunohistochemistry , Liver Neoplasms/metabolism , Logistic Models , Male , Middle Aged , Neoplasm Recurrence, Local/metabolism , Prognosis , Ribonucleoside Diphosphate Reductase/metabolism , Biomarkers, Tumor/metabolism , Young Adult
10.
Tumor ; (12): 258-263, 2013.
Article in Chinese | WPRIM | ID: wpr-848910

ABSTRACT

Objective: To investigate the relationship between the mutation of EGFR (epidermal growth factor receptor) gene and the expressions of ERCC1 (excision repair cross-complementation group 1) and RRM1 (ribonucleotide reductase M1) proteins in adenocarcinoma tissues from patients with stages I-III lung adenocarcinoma. Methods: The status of EGFR gene mutation in exons 19 and 21 in adenocarcinoma tissues from 99 patients with stages I-III lung adenocarcinoma was detected by amplification refractory mutation system using fluorescence-based quantitative-PCR instrument. The expressions of ERCC1 and RRM1 proteins were detected by immunohistochemistry. Results: The mutation rate of EGFR gene in all patients was 46.5%. The females or the non-smokers had a higher mutation rate of EGFR gene (P 0.05). There was also no relationship between the expressions of ERCC1 and RRM1 proteins (P > 0.05). Conclusion: A low level of ERCC1 protein is more likely to be expressed in lung adenocarcinoma patients with EGFR mutation, who may benefit from the platinumbased chemotherapy. Copyright © 2013 by TUMOR.

11.
Virologica Sinica ; (6): 40-46, 2011.
Article in Chinese | WPRIM | ID: wpr-382731

ABSTRACT

RNA interference(RNAi)is a process by which introduced small interfering RNA(siRNA)can cause the specific degradation of mRNA with identical sequences. The human herpes simplex virus type 1(HSV-1)RR is composed of two distinct homodimeric subunits encoded by UL39 and UL40, respectively. In this study, we applied siRNAs targeting the UL39 and UL40 genes of HSV-1. We showed that synthetic siRNA silenced effectively and specifically UL39 and UL40 mRNA expression and inhibited HSV-1 replication. Our work offers new possibilities for RNAi as a genetic tool for inhibition of HSV-1 replication.

12.
Genomics & Informatics ; : 170-176, 2010.
Article in English | WPRIM | ID: wpr-37185

ABSTRACT

The Ribonucleotide reductases (RNR) are essential enzymes that catalyze the conversion of nucleotides to deoxynucleotides in DNA replication and repair in all living organisms. The RNRs operate by a free radical mechanism but differ in the composition of subunit, cofactor required and regulation by allostery. Based on these differences the RNRs are classified into three classes-class I, class II and class III which depend on oxygen, adenosylcobalamin and S-adenosylmethionine with an iron sulfur cluster respectively for radical generation. In this article thirty seven sequences belonging to each of the three classes of RNR were analyzed by using various tools of bioinformatics. Phylogenetic analysis, dot-plot comparisons and motif analysis was done to identify a number of differences in the three classes of RNRs. In this research article, we have attempted to decipher evolutionary relationship between the three classes of RNR by using bioinformatics approach.


Subject(s)
Cobamides , Computational Biology , DNA Replication , Iron , Nucleotides , Oxygen , Ribonucleotide Reductases , S-Adenosylmethionine , Sulfur
13.
Article in Chinese | WPRIM | ID: wpr-393347

ABSTRACT

.036;r=-0.968,P=0.032).Conclusions Epo might decrease the chemo-sensitivity of SW1990 to gemcitabine possibly by up-regulating the expressions of MDR-1 and RRM1.

14.
Genet. mol. res. (Online) ; 7(1): 1-6, Jan. 2008. ilus
Article in English | LILACS | ID: lil-553764

ABSTRACT

Ribonucleotide reductase (RNR) of the yeast Saccharomyces cerevisiae is a tetrameric protein complex, consisting of two large and two small subunits. The small subunits Y2 and Y4 form a heterodimer and are encoded by yeast genes RNR2 and RNR4, respectively. Loss of Y4 in yeast mutant rnr4delta can be compensated for by up-regulated expression of Y2, and the formation of a small subunit Y2Y2 homodimer that allows for a partially functional RNR. However, rnr4delta mutants exhibit slower growth than wild-type (WT) cells and are sensitive to many mutagens, amongst them UVC and photo-activated mono- and bi-functional psoralens. Cells of the haploid rnr4delta mutant also show a 3- to 4-fold higher sensitivity to the oxidative stress-inducing chemical stannous chloride than those of the isogenic WT. Both strains acquired increased resistance to SnCl2 with age of culture, i.e., 24-h cultures were more sensitive than cells grown for 2, 3, 4, and 5 days in liquid culture. However, the sensitivity factor of three to four (WT/mutant) did not change significantly. Cultures of the rnr4delta mutant in stationary phase of growth always showed higher frequency of budding cells (budding index around 0.5) than those of the corresponding WT (budding index <0.1), pointing to a delay of mitosis/cytokinesis.


Subject(s)
Tin Compounds/toxicity , Genes, Fungal/genetics , Mutagens/toxicity , Ribonucleotide Reductases/genetics , Saccharomyces cerevisiae/enzymology , Cell Survival , Dimerization , Haploidy , Mutation , RNA, Fungal/biosynthesis , Ribonucleotide Reductases/chemistry , Saccharomycetales , Sensitivity and Specificity , Saccharomyces cerevisiae/cytology , Saccharomyces cerevisiae/genetics , Time Factors
15.
Article in English | WPRIM | ID: wpr-205421

ABSTRACT

For cancer gene therapy, cancer-specific over-expression of a therapeutic gene is required to reduce side effects derived from expression of the gene in normal cells. To develop such an expression vector, we searched for genes over-expressed and/or specifically expressed in cancer cells using bioinformatics and have selected genes coding for protein regulator of cytokinesis 1 (PRC1) and ribonuclease reductase 2 (RRM2) as candidates. Their cancer-specific expressions were confirmed in both breast cancer cell lines and patient tissues. We compared each promoter's cancer-specific activity in the breast normal and cancer cell lines using the luciferase gene as a reporter and confirmed cancer-specific expression of both PRC1 and RRM2 promoters. To test activities of these promoters in viral vectors, the promoters were also cloned into an adeno-associated viral (AAV) vector containing green fluorescence protein (GFP) as the reporter. The GFP expression levels by these promoters were various depending on cell lines tested and, in MDA-MB-231 cells, GFP activities derived from the PRC1 and RRM2 promoters were as strong as that from the cytomegalovirus (CMV) promoter. Our result showed that a vector containing the PRC1 or RRM2 promoter could be used for breast cancer specific overexpression in gene therapy.


Subject(s)
Breast Neoplasms/genetics , Cell Cycle Proteins/genetics , Cell Line, Tumor , Cloning, Molecular , Cytomegalovirus , Dependovirus , Female , Gene Targeting , Genetic Therapy , Genetic Vectors , Green Fluorescent Proteins , Humans , Promoter Regions, Genetic/genetics , Ribonucleoside Diphosphate Reductase/genetics , Transcriptional Activation
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