비소세포폐암종에서 Cyclin B1, Matrix Metalloproteinase-2, Vascular Endothelial Growth Factor 발현의 의미

송지선 關東大學校 醫科大學 醫科學硏究所 2003 關東醫大學術誌 Vol.7 No.2

Cyclin B1 is a key molecule for G2-M phase transition during the cell cycle by binding with cyclin dependent kinase-1(CDKI). Cyclin B1 expression is increased in various tumor types. However, the expression status of cyclin B1 in lung cancer and its clinical significance remain unknown. It is essential to invasion of tumor cells that a lysis of basement membrane and extracellular matrix by protease such as matrix metalloproteinase-2 (MMP-2). Vascular endothelial growth factor (VEGF) is known to be an endothelial cell-specific powerful mitogen and regulator of neovascularization in tumor cells. This study is aimed to clarify the role of the cell cycle regulator cyclin B1 in non-small cell lung carcinoma (NSCLC), and to reveal prognostic significance of cyclin B1, CDK1, MMP-2, and VEGF in NSCLC by analysing the relationship between their expression and clinicopathologic parameters. Immunohistochemical stains were performed in surgically resected 90 cases of NSCLC, including 56 cases of squamous cell carcinoma and 34 cases of adenocarcinoma. Cyclin B1 expression is closely related with CDKI expression and both showed higher positivity in group with higher Ki-67 LI(p<0.05). MMP-2 expression was significantly correlated with the survival time (p<0.05). VEGF expression was significantly higher in group with lymph node metastasis and in cyclin B1-positive group (p<0.05). In conclusion, although cyclin B1 expression may be not an independent prognostic factor in NSCLC, these data suggest that cyclin Bl may have a potential role in tumor development and progression in related with Ki-67 LI, expression of CDK1 and VEGF and that MMP-2 and VEGF may be poor prognostic factors in NSCLC.

Overexpressions of Cyclin B1, cdc2, p16 and p53 in Human Breast Cancer: The Clinicopathologic Correlations and Prognostic Implications

채승완,김동훈,손진희,최윤정,박용래,김경은,조영혜,표정수,김준호 연세대학교의과대학 2011 Yonsei medical journal Vol.52 No.3

Purpose: The molecular mechanisms that are responsible for the initiation and progression of breast cancers are largely unknown. This study was to analyze the cyclin B1, cdc2, p53 and p16 tumor suppressor genes in human breast cancer. Materials and Methods: To investigate the role of cyclin B1, cdc2, p53 and p16 in the pathogenesis and progression of breast carcinomas, 98 cases of breast cancers were examined by immunohistochemical method. The correlations of cyclin B1, cdc2, p53 and p16 expression with various clinico-pathologic findings were analysed. Results: In the normal breast tissues, cyclin B1, cdc2 and p16 were weakly expressed, while p53 was not expressed. On the other hand, cyclin B1, cdc2, p53 and p16 were overexpressed in breast cancer, showing correlation between the expression of cyclin B1 and cdc2 and breast cancers (p=0.00). The overexpressions of cdc2 and p16 were correlated with an infiltrative tumor border pattern and this was statistically significant (p<0.05). In addition, the overexpression of cdc2 was correlated with histologic high grade carcinomas (p=0.00). Conclusion:Cyclin B1 and cdc2 appeared to be involved in the genesis or progression of breast cancers. In addition, the overexpressions of p16 and p53 may play important roles in more aggressive tumor and the overexpression of cdc2 is associated with progression of tumor to a higher grade of breast carcinomas. The deranged overexpressions of cyclin B1, cdc2, p16 and p53 may play an important role in human breast carcinogenesis.

경도 B세포 림프종 분류시 파라핀 포매 조직에서 시행한 면역조직화학기법의 유용성

황태숙,이승숙,김지은,한혜승,김철우 대한병리학회 1998 Journal of Pathology and Translational Medicine Vol.32 No.12

항인체 사이클린 B2 항체를 이용한위점막 상피세포의 역동성

김대곤 ( Dae Ghon Kim ),김형식 ( Hyung Sik Kim ),문우성 ( Woo Sung Moon ),이승옥 ( Seong Ok Lee ),김정권 ( Jeong Kwon Kim ),양두현 ( Doo Hyun Yand ) 전북대학교 의과학연구소 2002 全北醫大論文集 Vol.26 No.2

인간의 B형 cyclin B1과 B2는 대부분의 분열세포들에서 발현된다. cyclin B1은 세포분열에 필수 유전자로 알려졌으나 cyclin B2는 그 기능이 잘 알려져 있지 않다. 따라서 그 기능을 파악하기 위하여 인간 cyclin B2 유전자를 분리하여 다양한 조직에 cyclin mRNA 발현을 관찰하였으며 폴리클론 항체를 제작하여 위장의 각 질환별 면역화학염색을 실시하였다. 정상 위 유문부에는 음성이었으나 intestinal metaplasia에서는 대부분에서 양성이었으며 선종 및 선암 등의 상당 예에서 양성 면역염색이 관찰되었으며 이는 MUC2 면역염색과 유사하였다. 이러한 결과로 인간의 cyclin B2는 전구위암질환인 intestinal metaplasia에 발현되며 선종이나 선암에서는 감소하는 경향을 보였다. 따라서 cyclin B2는 점액분비형성에 관련되며 일부 위암의 발암과정에 연관된다고 추정되었다.

Hip2 interacts with cyclin B1 and promotes its degradation through the ubiquitin proteasome pathway

Bae, Y.,Choi, D.,Rhim, H.,Kang, S. North-Holland Pub ; Elsevier Science Ltd 2010 FEBS letters Vol.584 No.22

Hip2, a ubiquitin conjugating enzyme, is involved in the suppression of cell death. The present study revealed that Hip2 regulates the stability of the apoptotic and cell cycle regulator cyclin B1. Hip2 was found to interact with cyclin B1 to promote its degradation through the ubiquitin proteasome pathway. As a result, Hip2 significantly blocked cell death induced by the cyclin B1 protein, suggesting that Hip2 is involved in the regulation of cyclin B1-mediated cell death. Structured summary: MINT-8045218, MINT-8045231: Hip2 (uniprotkb:P61086) physically interacts (MI:0915) with cyclin-B1 (uniprotkb:P14635) by pull down (MI:0096)

신세포암종에서 Anaphase Promoting Complex (APC)의 면역조직화학적 발현

송지선 關東大學校 醫科大學 醫科學硏究所 2003 關東醫大學術誌 Vol.7 No.1

The anaphase promoting complex(APC) appears to be responsible for the degradation of cyclin B after transition from G2 to M in cell cycle and to promote transition from metaphase to anaphase. It is known that cell cycle regulators such as cyclins and cyclin dependant kinase (CDK) at chekpoints are related to tumorigenesis or tumor advancement. However, a direct link between expression of APC components and oncogenesis and tumor progression has not been established. To examine the relationship between expression of APC and that of VEGF, cyclin B, Cdc2, and clinico-pathologic variables in renal cell carcinoma, this study evaluated 52 cases of renal cell carcinoma surgically resected from 1987 to 1998 at Wonju Christian Hospital, Wonju College of Medicine, Yonsei University. Immunohistochemical stains were performed for APC, Ki-67, VEGF, cyclin B, and Cdc2 using the avidin-biotin-complex method. APC revealed a positive reaction in 21 cases (40.4%). Ki-67 labelling index(LI) was significantly correlated with the positivity of APC, cyclin B, and Cde2. APC positive group showed higher Ki-67 LI (mean 101.6 vs 26.7) (p<0.05), higher VEGF-positivity (54.8% vs 12.5%) (p<0.05), higher Cdc2-positivity (65.0% vs 26.7%) (<0.05), later stage (56.3% vs 33.3%), and shorter mean survival time. Cdc2 expression was significantly higher in VEGF-positive group (53.3% vs 20.0%) and in poop with later stage (60.0% vs 31.4%) (p<0.05). These findings suggest that the APC in renal cell carcinoma may play a potential role in tumor progression by showing aberrant function of cell cycle control.

DRG2 Regulates G2/M Progression via the Cyclin B1-Cdk1 Complex

Jang, Soo Hwa,Kim, Ah-Ram,Park, Neung-Hwa,Park, Jeong Woo,Han, In-Seob Korean Society for Molecular and Cellular Biology 2016 Molecules and cells Vol.39 No.9

Developmentally regulated GTP-binding protein 2 (DRG2) plays an important role in cell growth. Here we explored the linkage between DRG2 and G2/M phase checkpoint function in cell cycle progression. We observed that knockdown of DRG2 in HeLa cells affected growth in a wound-healing assay, and tumorigenicity in nude mice xenografts. Flow cytometry assays and [$^3H$] incorporation assays indicated that G2/M phase arrest was responsible for the decreased proliferation of these cells. Knockdown of DRG2 elicited down-regulation of the major mitotic promoting factor, the cyclin B1/Cdk1 complex, but upregulation of the cell cycle arresting proteins, Wee1, Myt1, and p21. These findings identify a novel role of DRG2 in G2/M progression.

DRG2 Regulates G2/M Progression via the Cyclin B1-Cdk1 Complex

장수화,김아람,박능화,박정우,한인섭 한국분자세포생물학회 2016 Molecules and cells Vol.39 No.9

Developmentally regulated GTP-binding protein 2 (DRG2) plays an important role in cell growth. Here we explored the linkage between DRG2 and G2/M phase checkpoint function in cell cycle progression. We observed that knockdown of DRG2 in HeLa cells affected growth in a wound-healing assay, and tumorigenicity in nude mice xenografts. Flow cytometry assays and [3H] incorporation assays indicated that G2/M phase arrest was responsible for the decreased proliferation of these cells. Knockdown of DRG2 elicited down-regulation of the major mitotic promoting factor, the cyclin B1/Cdk1 complex, but up-regulation of the cell cycle arresting proteins, Wee1, Myt1, and p21. These findings identify a novel role of DRG2 in G2/M progression.

12-O-Tetradecanoyl phorbol-13-acetate (TPA)-induced growth arrest is increased by silibinin by the down-regulation of cyclin B1 and cdc2 and the up-regulation of p21 expression in MDA-MB231 human breast cancer cells

Kim, S.,Lee, H.S.,Lee, S.K.,Kim, S.H.,Hur, S.M.,Kim, J.S.,Kim, J.H.,Choe, J.H.,Shin, I.,Yang, J.H.,Lee, J.E.,Nam, S.J. G. Fischer 2010 Phytomedicine Vol.17 No.14

TPA is a potent regulator of cell growth, including cell proliferation and differentiation. In this study, we determined the effect of silibinin on TPA-induced growth arrest in breast cancer cells. Silibinin increased growth arrest of the G2/M phase in a dose-dependent fashion. Silibinin decreased the basal level of cyclin B1 and cdc2 expression, which is involved in S phase and G2/M transition. In addition, TPA-induced G2/M phase arrest was increased by silibinin. Under the same conditions, TPA-induced down-regulation of cyclin B1 and cdc2 was decreased by silibinin. In contrast, TPA-induced p21 expression was further increased by silibinin. To determine the regulatory mechanism of TPA-induced growth arrest, we pretreated cells with various inhibitors, such as UO126, SB203580, and LY294002. Interestingly, TPA-induced growth arrest was significantly increased by LY294002, but not by UO126 and SB203580. In addition, TPA-induced down-regulation of cyclin B1 was inhibited by LY294002; however, the basal level of p21 was increased by TPA and TPA-induced p21 expression was further increased by LY294002. Finally, adenoviral constitutively active-Akt (Ad-CA-Akt) overexpression regulated the up-regulation of cyclin B1 and the down-regulation of p21. Therefore, we have demonstrated that silibinin has an additive effect on TPA-induced growth arrest through the PI-3-kinase/Akt-dependent pathway.

암 억제 유전자 TIS21/BTG2/PC3에 의한 간암 발생 억제 기전

박태준 ( Tae Jun Park ) 대한간암학회 2011 대한간암학회지 Vol.11 No.2

A functional and biochemical features of TIS21(/BTG2/PC3) was explored in hepatocarcinogenesis. Growth of hepatocellular carcinoma (HCC), developed by a single injection of diethylnitrosamine (DEN) was significantly higher in the TIS21 knockout mice at 9 months. Expression of BTG2/TIS21 was significantly lower in both human and mouse hepatocellular carcinoma than in the surrounding normal tissues. Over-expression of TIS21 inhibited cell proliferation and tumorigenic potential of Huh7 hepatoma cells. At the molecular mechanistic level, TIS21 inhibited FoxM1 phosphorylation, by reducing cyclin B1-cdk1 activity. Furthermore, TIS21 inhibited FoxM1 transcriptional activity. In conclusion, TIS21 negatively regulated hepatocarcinogenesis in part by disruption of the FoxM1-cyclin B1 regulatory loop, thereby inhibiting proliferation of transformed cells developed in mouse and human livers.