• Animal cells and systems
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• 제2권4호
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• pp.495-500
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• 1998

D-type G1 cyclins are known to be crucial for the progression of mitotic cell cycle in mammals. Although many studies have been performed to elucidate the roles of D-type cyclins, it is largely unknown whether D-type cyclins are directly involved in the regulation of meiotic germ cell development. In the present study, we examined the expression patterns of D-type cyclins (cyclin D1 and D3) during male germ cell development by northern blot and in situ Hybridization analyses. In the adult testes, we detected a 4.2 kb cyclin D1 mRNA and two different sizes (2.3 kb and 1.8 kb) of cyclinD3 mRNAs. The short form of the cyclin D3 transcript was testis-specific. Along with the testicular development, expression of cyclin D3 mRNA was increased whereas cyclin D1 mRNA was gradually decreased. in situ hybridization study also revealed that the expression of cyclin D3 was restricted to the postmeiotic germ cells. Furthermore, the 2.3 kb transcript was highly expressed in the round spermatids and decreased in the elongated spermatids/residual bodies, while the 1.8 kb transcript was expressed in elongated spermatids/residual bodies more abundantly. Sucrose-gradient separation of polysomal RNA fractions demonstrated that some portions of the 2.3 kb transcript are translationally active, while the 1.8 kb transcript is likely to be inactive. Taken together, the present data suggest a functional importance of cyclin D3 expression in the differentiated postmeiotic male germ cells.

• Applied Biological Chemistry
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• 제43권3호
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• pp.174-178
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• 2000

인체 세포의 세포주기를 조절하는 Cyclin-dependent Kinase(CDK) 중 CDK4/Cyclin D1 효소 저해 물질을 찾기 위하여 국내에 자생하는 37과 87종의 식물 추출물을 탐색한 결과, 50%$(5\;{\mu}g/ml)$ 이상의 CDK4/Cyclin D1 호소 저해활성을 보인 것은 단삼(Salvia miltiorrhiza), 노박덩굴(Celastrus orbiculatus), 삼백초(Saurus chinensis), 목단(Paeonia suffruticosa) 및 오이풀(Sanguisorba officinalis)이었다. 이들 중에서 목단과 오이풀 추출물이 가장 높은 56%의 저해율을 각각 나타내었다. 또한 추출물에서 활성물질을 추출 정제하여 2차원 NMR 등을 포함한 각종 기기분석을 통하여 cryptotanshinone으로 동정하였다.

• The Korean Journal of Physiology and Pharmacology
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• 제7권5호
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• pp.289-293
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• 2003

Mutations in the NF2 tumor suppressor gene cause neurofibromatosis type 2, an autosomal dominant inherited syndrome predisposed to the multiple tumors of the nervous system. Merlin, the NF2 gene product was reported to block Ras-mediated cell transformation and represses Ras-induced expression of cyclin D1. However, the potential mechanism underlying the anti-Ras function of merlin on the cyclin D1 is still unclear. In this study, we investigated whether merlin decreases Ha-ras-induced accumulation of cyclin D1 at the transcriptional level, and demonstrated that merlin suppressed Ras-induced cyclin D1 promoter activity mediated by the cyclic AMP-responsive element (CRE) in SK-N-BE(2)C neuroblastoma cells. Furthermore, we found that merlin attenuated active Ras and forskolin-induced CRE-driven promoter activity. These results suggest that the transcriptional repression of the cyclin D1 expression by merlin may contribute to the inhibition of Ras-induced cell proliferation.

• 한국자원식물학회지
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• 제28권6호
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• pp.682-689
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• 2015

Abeliophyllum distichum Nakai (A. distichum) has been reported to exert the inhibitory effect on angiotensin converting enzyme and aldose reductase. Recently, our group found that branch extracts of A. distichum (EAFAD-B) induce apoptosis through ATF3 activation in human colon cancer cells. However, anti-cancer reagents exert their activity through the regulation of various molecular targets. Therefore, the elucidation of potential mechanisms of EAFAD-B for anti-cancer activity may be necessary. To elucidate the potential mechanism of EAFAD-B for anti-cancer activity, we evaluated the regulation of cyclin D1 in human colon cancer cells. EAFAD-B decreased cellular accumulation of cyclin D1 protein. However, cyclin D1 mRNA was not changed by EAFAD-B. Inhibition of proteasomal degradation by MG132 attenuated EAFAD-B-mediated cyclin D1 downregulation and the half-life of cyclin D1 was decreased in the cells treated with EAFAD-B. In addition, EAFAD-B induced cyclin D1 phosphorylation at threonine-286 and the point mutation of threonine-286 to alanine attenuated EAFAD-B-mediated cyclin D1 proteasomal degradation. Inhibitions of both ERK1/2 by PD98059 and NF-κB by a selective inhibitor, BAY 11-7082 suppressed cyclin D1 downregulation by EAFAD-B. From these results, we suggest that EAFAD-B-mediated cyclin D1 downregulation may result from proteasomal degradation through its threonine-286 phosphorylation via ERK1/2-dependent NF-κB activation. The current study provides new mechanistic link between EAFAD-B and anti-cancer activity in human colon cancer cells.

• 한국자원식물학회지
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• 제30권6호
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• pp.640-646
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• 2017

In this study, we elucidated anti-cancer activity and potential molecular mechanism of 70% ethanol extracts from Taxilli Ramulus (Taxillus chinensis (DC.) Danser) (TR-E70) against human colorectal cancer cells. Anti-cell proliferative effect of TR-E70 was evaluated by MTT assay. The effect of TR-E70 on the expression of cyclin D1 in the protein and mRNA level was evaluated by Western blot and RT-PCR, respectively. TR-E70 suppressed the proliferation of human colorectal cancer cell lines, HCT116 and SW480. Although TR-E70 decreased cyclin D1 expression in protein and mRNA level, decreased level of cyclin D1 protein by TR-E70 more dramatically occurred than that of cyclin D1 mRNA. Cyclin D1 downregulation by TR-E70 was attenuated in presence of MG132. In addition, TR-E70 phosphorylated threonine-286 (T286) of cyclin D1. TR-E70-mediated cyclin D1 degradation was blocked in presence of LiCl as an inhibitor $GSK3{\beta}$ but not PD98059 as an ERK1/2 inhibitor and SB203580 as a p38 inhibitor. Our results suggest that TR-E70 may downregulate cyclin D1 as one of the potential anti-cancer targets through $GSK3{\beta}$-dependent cyclin D1 degradation. From these findings, TR-E70 has potential to be a candidate for the development of chemoprevention or therapeutic agents for human colorectal cancer.

• 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.

• 한국자원식물학회지
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• 제31권3호
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• pp.218-227
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• 2018

In this study, we investigated the effect of the extracts from Vaccinium oldhamii on cell proliferation and the regulatory mechanisms of cyclin D1 protein level in human cancer cells. The branch extracts from Vaccinium oldhamii (VOB) showed higher inhibitor effect against the cell growth than leave extracts (VOL) and fruit extracts (VOF) in human colorectal cancer, breast cancer, prostate cancer, non-small lung cancer, pancreatic cancer and liver cancer cells. In addition, VOB decreased cyclin D1 level at both protein and mRNA level. MG132 treatment attenuated VOB-mediated cyclin D1 downregulation. A point mutation of threonine-286 to alanine attenuated cyclin D1 degradation by VOB. In addition, the inhibition of nuclear export by leptomycin B (LMB) attenuated cyclin D1 degradation by VOB. But, the treatment of PD98059 (ERK1/2 inhibitor), SB203580 (p38 inhibitor), SP600125 (JNK inhibitor), LiCl ($GSK3{\beta}$ inhibitor), LY294002 (PI3K inhibitor) or BAY 11-7082 ($I{\kappa}K$ inhibitor) did not affect VOB-induced cyclin D1 degradation. In conclusion, VOB induced cyclin D1 degradation through redistribution of cyclin D1 from the nucleus to cytoplasm via T286 phosphorylation of cyclin D1, which resulted in the inhibition of cancer cell proliferation.

• 한국자원식물학회지
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• 제33권4호
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• pp.271-278
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• 2020

이상의 연구 결과로 먹넌출 열매 추출물은 GSK3β 의존성 Cyclin D1 단백질의 분해를 통해 대장암세포의 생육 억제와 관련이 있는 것으로 확인된다. 본 결과는 대장암의 항암제 개발을 위한 소재로 먹넌출 열매의 활용이 가능할 것으로 판단된다.

• 한국약용작물학회지
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• 제25권5호
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• pp.328-334
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• 2017

Background: In this study, we evaluated the anti-cancer activity and potential molecular mechanism of 70% ethanol extracts of the root of Aralia cordata var. continentalis (Kitagawa) Y. C. Chu (RAc-E70) against human colorectal cancer cells. Methods and Results: RAc-E70 suppressed the proliferation of the human colorectal cancer cell lines, HCT116 and SW480. Although RAc-E70 reduction cyclin D1 expression at the protein and mRNA levels, RAc-E70-induced reduction in cyclin D1 protein level occurred more dramatically than that of cyclin D1 mRNA. The RAc-E70-induced downregulation of cyclin D1 expression was attenuated in the presence of MG132. Additionally, RAc-E70 reduced HA-cyclin D1 levels in HCT116 cells transfected with HA-tagged wild type-cyclin D1 expression vector. RAc-E70-mediated cyclin D1 degradation was blocked in the presence of LiCl, a $GSK3{\beta}$ inhibitorbut, but not PD98059, an ERK1/2 inhibitor and SB203580, a p38 inhibitor. Furthermore, RAc-E70 phosphorylated cyclin D1 at threonine-286 (T286), and LiCl-induced $GSK3{\beta}$ inhibition reduced the RAc-E70-mediated phosphorylation of cyclin D1 at T286. Conclusions: Our results suggested that RAc-E70 may downregulate cyclin D1 expression as a potential anti-cancer target through $GSK3{\beta}$-dependent cyclin D1 degradation. Based on these findings, RAc-E70 maybe a potential candidate for the development of chemopreventive or therapeutic agents for human colorectal cancer.

• Asian Pacific Journal of Cancer Prevention
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• 제14권1호
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• pp.419-422
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• 2013

Conventional classifications of gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are rather unsatisfactory because of the variation in survival within each subgroup. Molecular markers are being found able to predict patient outcome in more and more tumours. The aim of this study was to characterize the expression of the proteins cyclin D1, cyclin E and P53 in GEP-NETs and assess any prognostic impact. Tumor specimens from 68 patients with a complete follow-up were studied immunohistochemically for cyclin D1, cyclin E and P53 expression. High cyclin D1 and cyclin E immunostaining (${\geq}$ 5% positive nuclei) was found in 48 (71%) and 24 (35%) cases, and high P53 staining (${\geq}$ 10% positive nuclei) in 33 (49%). High expression of P53 was more common in gastric neuroendocrine tumors and related to malignant behavior, being associate with a worse prognosis on univariate analysis (RR=1.9, 95%CI=1.1-3.2). High expression of cyclin E was significantly associated with shorter survival in the univariate analysis (RR=2.0, 95%CI=1.2-3.6) and multivariate analysis (RR=2.1, 95%CI=1.1-4.0). We found no significant correlation between the expression of cyclin D1 and any clinicopathological variables. Our study indicated a prognostic relevance for cyclin E and P53 immunoreactivity. Cyclin E may be an independent prognostic factor from the 2010 WHO Classification which should be evaluated in further studies.