• Bulletin of the Korean Chemical Society
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• 제34권4호
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• pp.1165-1169
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• 2013

To elucidate the role of PKG isoforms in transcriptional control of cyclin D1, we employed a series of expression vectors of PKG $1{\alpha}$ and PKG $1{\beta}$ which encode HA-tagged wild type and constitutively active (SD and ${\Delta}N$) mutants. Our present study demonstrates that both the constitutively active mutants of PKG $1{\beta}$ downregulate the transcription of cyclin D1 when transiently transfected in NIH3T3 cells, whereas PKG $1{\alpha}$ mutants show weak inhibition. We further studied the transcriptional regulators of cyclin D1, such as, c-fos, NF-${\kappa}B$, and CRE by using the luciferase reporter assay. Constitutively active mutants of PKG $1{\beta}$ showed marked transcriptional downregulation of c-fos in NIH3T3 cells, whereas PKG $1{\alpha}$ downregulated c-fos to a lesser extent. We also found that the constitutively active mutants of PKG negatively regulated the activation of NF-${\kappa}B$ and CRE, suggesting their involvement in the regulation of cyclin D1.

• 생명과학회지
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• 제16권5호
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• pp.828-833
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• 2006

옥수수 (Zea mays L.) 꽃은 암술 세포사멸과 수술 세포 성장정지 등을 통하여 양성상태에서 단성 상태로 성결정 과정을 완성한다. 본 논문에서는 옥수수 성 결정 동안 세포주기 유전자들의 시간적, 공간적 발현조절을 조사하였다. 세포주기의 양성조절 인자 즉 cyclin A, cyclin B, cyclin dependent kinase A (CDK A), Mad2 유전자들은 성장하는 암술과 수술에서 높게 발현되는 반면 죽어가는 암술과 성장이 정지되는 수술에서는 이들의 발현이 사라졌다. 이와 반대로, Wee1과 CDK inhibitor (CKI) 같은 세포주기 음성 조절유전자들은 야생형 암꽃과 tasselseed2 돌연변이 수꽃의 성장이 정지하고 있는 수술에서 발현이 증가되었지만, 흥미롭게도, 이들 유전자들은 죽어가는 암술세포에서는 발현되지 않았다. 이들 결과들을 통하여 옥수수 성 결정 과정 중에서 암술 세포사멸과 수술세포 성장정지는 세포주기조절과 밀접한 관계가 있으며, 특히 성장이 정지하는 수술과 죽어가는 암술에서의 음성 세포주기 조절 유전자들의 다른 발현양상은 이 둘의 성 결정 메커니즘이 구별 될 것이라고 사료된다.

• Reproductive and Developmental Biology
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• 제35권4호
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• pp.499-502
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• 2011

Aurora A kinase is a mitotic serine/threonine kinase whose proposed functions include the maturation of centrosomes, G2/M transition, alignment of chromosomes at metaphase, and cytokinesis. In this study, we investigated the effect of MLN8237, an aurora A kinase inhibitor, on the postovulatory aging of oocytes based on the frequency of oocyte fragmentation, cdk1 kinase activity, and cyclin B degradation. The fragmentation of ovulated oocytes during prolonged culture was inhibited by treatment with MLN8237 in a concentration-dependent manner. The frequency of fragmented oocytes was significantly lower in oocytes treated with 2 ${\mu}M$ MLN8237 (13%) than in control oocytes (64%) after two days of culture. Most of the control (non-fragmented) oocytes (91%) were activated after two days of culture. In comparison, only 22% of the MLN8237-treated oocytes were activated; the rest of the oocytes (78%) were still in metaphase with an abnormal spindle and dispersed chromosomes. Next, cdk1 activity and the level of cyclin B were examined. The level of cyclin B and cdk1 activity in MLN8237-treated oocytes were nearly equal to those in control oocytes. Our results indicate that MLN8237 inhibited the fragmentation of ovulated oocytes during prolonged culture, although it blocked the spontaneous decrease in activity of cdk1 and degradation of cyclin B. This mechanism of inhibition is different from that in oocytes treated with nocodazole, which have high levels of cdk1 activity and cyclin B.

• Asian Pacific Journal of Cancer Prevention
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• 제16권6호
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• pp.2209-2213
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• 2015

DNA methylation of tumor suppressor gene promoters is the most frequent phenomenon leading to inactivation of function, consequently driving malignant cell transformation. Cyclin D2 is implicated in tumor suppression. In our study, we carried out the MSP assay to evaluation the methylation status at CpG islands in the cyclin D2 promoter in breast cancer cases from the Vietnamese population. The results showed that the frequency of methylation reached 62.1% (59 of 95 breast cancer tumors), but was low in non-cancer specimens at 10% (2 of 20 non-cancer specimens). Additionally, with an RR (relative risk) and OR (odd ratios) of 6.21 and 14.8, DNA hypermethylation of cyclin D2 increased the possibility of malignant transformation. Our results confirmed the cyclin D2 hypermethylation could be used as the potential biomarker which could be applied in prognosis and early diagnosis of Vietnamese breast cancer patients.

• Journal of Microbiology and Biotechnology
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• 제32권6호
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• pp.718-729
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• 2022

Esophageal squamous cell carcinoma (ESCC) is the most common primary esophageal malignancy with poor prognosis. Here, due to the necessity for exploring potential therapies against ESCC, we obtained the gene expression data on ESCC from the TCGA and GEO databases. Venn diagram analysis was applied to identify common targets. The protein-protein interaction network was constructed by Cytoscape software, and the hub targets were extracted from the network via cytoHubba. The potential hub nodes as drug targets were found by pharmacophore-based virtual screening and molecular modeling, and the antitumor activity was evaluated through in vitro studies. A total of 364 differentially expressed genes (DEGs) in ESCC were identified. Pathway enrichment analyses suggested that most DEGs were mainly involved in the cell cycle. Three hub targets were retrieved, including CENPF, CCNA2 (cyclin A), and CCNB1 (cyclin B1), which were highly expressed in esophageal cancer and associated with prognosis. Moreover, amentoflavone, a promising drug candidate found by pharmacophore-based virtual screening, showed antiproliferative and proapoptotic effects and induced G1 in esophageal squamous carcinoma cells. Taken together, our findings suggested that amentoflavone could be a potential cell cycle inhibitor targeting cyclin B1, and is therefore expected to serve as a great therapeutic agent for treating esophageal squamous cell carcinoma.

• Asian Pacific Journal of Cancer Prevention
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• 제14권10호
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• pp.6001-6005
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• 2013

Our aim was to explore anti-cell proliferative and anti-angiogenic potential of andrographolide by analyzing the expression pattern of cell proliferative (PCNA, Cyclin D1) and angiogenic (VEGF) markers during 7, 12-dimethylbenz(a)anthracene (DMBA) induced hamster buccal pouch carcinogenesis. DMBA painting three times a week for 14 weeks in the buccal pouch of golden Syrian hamsters resulted in oral tumors which were histopathologically diagnosed as well differentiated squamous cell carcinoma. Immunohistochemical (PCNA, VEGF) and RT-PCR (Cyclin D1) studies revealed over expression of PCNA, VEGF and Cyclin D1 in the buccal mucosa of hamsters treated with DMBA alone. Oral administration of andrographolide at a dose of 50 mg/kg bw to hamsters treated with DMBA not only suppressed the histological abnormalities but also down regulated the expression of PCNA, VEGF and Cyclin D1. The results of the present study suggest that andrographolide suppressed tumor formation in the buccal mucosa of hamsters treated with DMBA through its anti-cell proliferative and anti-angiogenic potential.

• 생명과학회지
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• 제11권4호
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• pp.362-370
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• 2001

Regulation of cell proliferation is a complex process involving the regulated expression and /or modification of discrete gene products. which control transition between different stages of the cycle. The purpose of this short review is to provide an overview of somatic cell cycle events and their controls. Cycline have appeared as major positive regulators in this network, because their association to the cyclin-dependent kinases(Cdks) allows the subsequent activation on the Cdk/cyclin complexes and their catalatic activity. In mammalian cells, early to mid G1 progression and late G1 progression leading to S phase entry are directed by D-type cyclins-Cdk4, 6 and cyclin E-Cdk 2 both of which can phosphorylate the retinoblastoma protein (pRB). pRB is a transcriptional repressor which, in its unphosphorylated state, binds to members of the E2F transcription factor family and blocks E2F-dependent transcription of genes controlling the G1 to S phase transition an subsequent DNA synthesis. Cyclin A is produced in late G1 and expressed during S and G2 phae, and expression of B-type cyclins is typically maximal during the G2 to M phase transition and it controls the passage through M phase. They primarily associate with the activate Cdk2, and Cdc2, respectively. On the other hand, the Cdk inhibitors negatively control the activity of C아/cyclin complex by coordinating internal and/or external signals and impending proliferation at several key checkpoints. These current and further findings will provide novel approaches to understanding and treating major diseases.

• Asian Pacific Journal of Cancer Prevention
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• 제15권8호
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• pp.3817-3823
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• 2014

Background: The MDM2 oncogene, a negative regulator of p53, has a functional polymorphism in the promoter region (SNP309) that is associated with multiple kinds of cancers including non-melanoma skin cancer. SNP309 has been shown to associate with accelerated tumor formation by increasing the affinity of the transcriptional activator Sp1. It remains unknown whether there are other factors involved in the regulation of MDM2 transcription through a trans-regulatory mechanism. Methods: In this study, SNP309 was verified to be associated with overexpression of MDM2 in tumor cells. Bioinformatics predicts that the T to G substitution at SNP309 generates a stronger E2F1 binding site, which was confirmed by ChIP and luciferase assays. Results: E2F1 knockdown downregulates the expression of MDM2, which confirms that E2F1 is a functional upstream regulator. Furthermore, tumor cells with the GG genotype exhibited a higher proliferation rate than TT, correlating with cyclin D1 expression. E2F1 depletion significantly inhibits the proliferation capacity and downregulates cyclin D1 expression, especially in GG genotype skin fibroblasts. Notably, E2F1 siRNA effects could be rescued by cyclin D1 overexpression. Conclusion: Taken together, a novel modulator E2F1 was identified as regulating MDM2 expression dependent on SNP309 and further mediates cyclin D1 expression and tumor cell proliferation. E2F1 might act as an important factor for SNP309 serving as a rate-limiting event in carcinogenesis.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• 제44권4호
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• pp.182-190
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• 2018

Objectives: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. Inconsistency in various histopathologic features for predicting nodal metastasis and overall prognosis and a better understanding of molecular mechanisms of tumourigenesis have shifted the focus to a search for more definitive predictive markers. To identify the role of two immunohistochemical (IHC) markers, E-cadherin and cyclin D1, as predictive markers of aggressiveness in HNSCC and to assess clonal expansion of tumour cells. Materials and Methods: A total of 66 cases of HNSCC with neck node dissection were studied. IHC was performed on primary tumour sections and lymph nodes showing metastatic deposits. Histopathological parameters such as tumour grade and TNM stage together with nodal status were compared according to expression of the two markers. Fischer's chi-square test was used to assess the correlation between the two markers and histopathological parameters. Results: Out of 66 cases studied, 37 showed LN metastasis. Most of the patients were male, and the most common tumour site was buccal mucosa. We found a significant association between loss of E-cadherin and node metastasis (P<0.001) and higher TNM stage (P<0.001). Cyclin D1 overexpression was significantly associated with only nodal metastasis (P=0.007). No significant association with tumour grade was found for either marker. The subgroup of E-cadherin loss with cyclin D1 overexpression was associated with the maximum incidence of nodal metastasis and higher TNM stage, highlighting the importance of using a combination of these two markers. A significant association was noted between the expression of markers at the primary site and at nodal deposits, indicating clonal expansion. Conclusion: A combination of the two markers E-cadherin and cyclin D1 can predict prognosis in HNSCC, although tumour heterogeneity may affect this association in some cases.

• 해부∙생물인류학
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• 제26권1호
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• pp.41-49
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• 2013

치아발생 및 형태형성 과정에서 치아상피와 치아간엽을 구성하는 세포는 동적인 세포주기의 변화가 일어난다. 현재까지 세포증식은 치아발생에 중요한 현상으로 알려져 있지만, 치아발생 중에 일어나는 복잡한 분자적 기전과 연관해서 세포주기의 각 시기가 어떻게 관여하는지에 대해서는 충분한 연구가 이루어지지 않았다. 그러므로 본 연구는 치아발생 기전과 세포주기의 시기의 변화와의 관계를 밝히고자 하였다. 치아발생 과정에서 일어나는 형태변화를 확인하기 위해 싹시기, 모자시기, 종시기의 쥐 앞니 및 어금니 치배를 헤마톡실린-에오신으로 염색하여 조직학적으로 관찰하였다. 또한 세포주기 시기의 표지자인 Ki-67, 싸이클린 A, 싸이클린 D1의 발현양상을 관찰하기 위해 면역조직화학염색을 시행하였다. 싹시기, 모자시기, 종시기에서 증식하는 세포들은 Ki-67과 싸이클린 A를 발현하는 것을 확인하였다. 싸이클린 D1은 앞니의 상아질모세포 및 모자시기의 사기질결절에서 특이적인 발현을 보였으며, 이곳에서는 Ki-67이나 싸이클린 A가 발현되지 않는다는 것을 발견하였다. 본 연구는 치아발생 중 각 주요 시기에서 세포주기의 변화를 관찰하였으며, 이는 치아발생에 관여하는 기전에 대한 중요한 정보를 제공한다. 또한 본 연구의 결과는 지금까지의 앞니의 사기질모세포 및 사기질결절의 특성에 대한 지식을 이해하는 데에 중요한 자료가 될 것으로 사료된다.