• YAKHAK HOEJI
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• v.50 no.1
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• pp.52-57
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• 2006

The activation of cyclin dependent kinase 4 (CDK4) is found in more than half of all human cancers. Therefore CDK4 is an attractive target for the development of a novel anticancer agent. For mass screening of CDK4 inhibitor, we set up in vitro kinase assay for CDK4 activity using a cyclin D1-CDK4 fusion protein, which is constitutively active and exhibits enhanced stability. From the screening of representative compound library of Korea Chemical Bank, we found that 7-chloro-4-nitro-benzo[1,2,5]oxadiazole 1-oxide (FBP-1248) selectively inhibited CDK4 activity in vitro by ATP competitive manner. This compound prevented the phosphorylation of retinoblatsoma tumor suppressor protein, Rb, and inhibited cell growth through cell cycle arrest. In summary, we developed an efficient assay system for CDK4 activity in vitro and identified the CDK4 inhibitory compound, FBP-1248.

• Journal of Life Science
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• v.19 no.7
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• pp.871-877
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• 2009

We investigated the effects of sodium butyrate, a histone deacetylase inhibitor, on the cell cycle progression in human monocytic leukemia U937 cells. Exposure of U937 cells to sodium butyrate resulted in growth inhibition, G1 arrest of the cell cycle and induction of apoptosis in a dose-dependent manner as measured by MTT assay and flow cytometry analysis. The increase in G1 arrest was associated with the down-regulation in cyclin D1, E, A, cyclin-dependent kinase (Cdk) 4 and 6 expression, and up-regulation of Cdk inhibitors such as p21 and p27. Sodium butyrate treatment also inhibited the phosphorylation of retinoblastoma protein (pRB) and p130, however, the levels of transcription factors E2F-1 and E2F-4 were not markedly modulated. Furthermore, the down-regulation of phosphorylation of pRB and p130 by this compound was associated with enhanced binding of pRB and E2F-1, as well as p130 and E2F-4, respectively. Overall, the present results demonstrate a combined mechanism involving the inhibition of pRBjp130 phosphorylation and induction of Cdk inhibitors as targets for sodium butyrate that may explain some of its anti-cancer effects in U937 cells.

• Journal of Life Science
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• v.20 no.7
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• pp.977-982
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• 2010

We investigated the anti-cancer effects of two dibenzocyclooctadiene lignans, gomisin A and gomisin N, isolated from Schizandra chinensis Baill, in human promyelocytic U937 cells. Gomisin N, but not gomisin A, inhibited cell growth in a concentration-dependent manner, which was associated with the induction of G1 arrest of the cell cycle. G1 arrest induced by gomisin N was correlated with down-regulation of cyclin E, cyclin-dependent kinase (Cdk) 2 and Cdk4, and a concomitant up-regulation of Cdk inhibitors such as p16 (INK4A) and p21 (WAF1/CIP1). Furthermore, gomisin N inhibited phosphorylation of retinoblastoma protein (pRB) and p130, and expression of transcription factor E2Fs. The results indicated that growth inhibition by gomisin N is related to cell cycle arrest at G1 in U937 cells and these findings suggest that gomisin N may be a useful chemotherapeutic agent.

• Development and Reproduction
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• v.18 no.1
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• pp.65-71
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• 2014

Cell cycle process is regulated by a number of protein kinases and among them, serine/threonine kinases carry phosphate group from ATP to substrates. The most important three kinase families are Cyclin-dependent kinase (Cdk), Polo-like kinase (Plk), and Aurora kinase. Polo-like kinase family consists of 5 members (Plk1-Plk5) and they are involved in multiple functions in eukaryotic cell division. It regulates a variety of aspects such as, centrosome maturation, checkpoint recovery, spindle assembly, cytokinesis, apoptosis and many other features. Recently, it has been reported that Plks are related to tumor development and over-expressed in many kinds of tumor cells. When injected the anti-Plk antibody into human cells, the cells show aneuploidy, and if inhibit Plks, most of the mitotic cell division does not proceed properly. For that reasons, many inhibitors of Plk have been recently emerged as new target for remedy of the cancer therapeutic research. In this paper, we reviewed briefly the characteristics of Plk families and how Plks work in regulating cell cycles and cancer formation, and the possibilities of Plks as target for cancer therapy.

• Journal of Periodontal and Implant Science
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• v.29 no.3
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• pp.593-607
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• 1999

치주인대세포는 치주인대의 유지와 개조에 있어서 중요한 역할을 담당하는 섬유아세포성 세포로서, 세포에 가해진 여러가지 조건에 따라 다양한 표현형의 변화를 나타내는 것으로 알려져 있다. 기계적 응력은 치주인대세포의 세포증 식과 밀접히 연관되어 있는 것으로 알려져 있으며, 이는 세포주기 조절인자들의 발현을 증가 시킴으로써 이루어질 것으로 생각되나 그 자세 한 작용기전은 알려져 있지 않다. 그러므로 이 연구의 목적은 기계적 응력이 사람 치주인대세 포의 세포증식과 세포주기 조절인자의 발현에 미치는 영향을 연구하기 위하여 사람 치주인대 세포에 기계적 응력을 가한 후 세포증식을 관찰하고 , 세포주기조절인자들인 p 53 , $p21^{WAF1/CIP1}$ cyclin-dependent kinases(cdks), cyclins 및 proliferating cell nuclear antigen(PCNA)의 단백질 발현 변화를 연구하였다. 본 연구에 사용한 사람 치주인 대세포는 교정치료를 목적으로 발거한 건전한 사람 소구치의 치주인대로부터 explantation culture하여 얻은 후 계대배양을 시행하여 제6 계대의 세포를 사용하였다. 배양한 사람 치주인 대세포를 55-mm Petriperm dish당 $1{\times}10^4$ 개를 분주하고, dish당 1kg의 기계적 응력을 가하면서 12일동안 세포배양을 시행하였다. 사람 치주인대세포의 세포증식은 기계적 응력을 가한 후 8-12일 사이에 현저히 증가하였으며, PCNA 단백질의 발현은 기계적 응력을 가한 후 6-10일 사이에 현저히 증가하였다. 또한 기계적 응력은 사람 치주 대세포의 cdk4, cdk6, cdk2 및 cyclin D1 단백질의 발현을 다소 증가 시켰으나, p53 및 $p21^{WAF1/CIP1}$ 단백질의 발현은 큰 변화가 없었다. 이상의 결과 서 기계적 응력은 사람 치주인대세포 의 p53 및 $p21^{WAF1/CIP1}$ 단백질 발현의 변화 없이 cdks 단백질 발현을 증가시킴으로써 세포증식을 증가시키는 것으로 생각된다.

• Natural Product Sciences
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• v.18 no.1
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• pp.16-21
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• 2012

Honokiol, a naturally occurring neolignan mainly found in Magnolia species, has been shown to have the anti-angiogenic, anti-invasive and cancer chemopreventive activities, but the molecular mechanism of actions has not been fully elucidated yet. In the present study, we investigated the effect of honokiol on the growth inhibitory activity in cultured SNU-638 human gastric cancer cells. We found that honokiol exerted potent antiproliferative activity against SNU-638 cells. Honokiol also arrested the cell cycle progression at the G0/G1 phase and induced the apoptotic cell death in a concentration-dependent manner. The cell cycle arrest was well correlated with the downregulation of Rb, cyclin D1, cyclin A, cyclin E, and CDK4 expression, and the induction of cyclin-dependent kinase inhibitor p27. The increase of sub-G1 peak by honokiol was closely related to the induction of apoptosis, which was evidenced by the induction of DNA fragmentation, the cleavage of poly(ADPribose) polymerase, and the sequential activation of caspase cascade. These findings suggest the cell cycle arrest and induction of apoptosis might be one possible mechanism of actions for the anti-proliferative activity of honokiol in human gastric cancer cell.

• Bulletin of the Korean Chemical Society
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• v.28 no.5
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• pp.723-724
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• 2007

• Korean Journal of Radiology
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• v.24 no.12
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• pp.1306-1308
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• 2023

• Journal of Life Science
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• v.16 no.4
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• pp.589-597
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• 2006

Genistein, a natural isoflavonoid phytoestrogen, is a strong inhibitor of protein tyrosine kinase and DNA topoisomerase activities. There are several studies documenting molecular alterations leading to cell cycle arrest and induction of apoptosis by genistein as a chemopreventive agent in a variety of cancer cell lines; however, its mechanism of action and its molecular targets on human bladder carcinoma and leukemic cells remain unclear. In the present study, we have addressed the mechanism of action by which genistein suppressed the proliferation of T24 bladder carcinoma and U937 leukemic cells. Genistein significantly inhibited the cell growth and induced morphological changes, and induced the G2/M arrest of the cell cycle in both T24 and U937 cells with a relatively stronger cytotoxicity in U937. The G2/M arrest in T24 cells was associated with the inhibition of cyclin A, cyclin B1 and Cdc25C protein expression without alteration of tumor suppressor p53 and cyclin-dependent kinase (Cdk) inhibitor p21(WAF1/CIP1). However, the inhibitory effects of genistein on the cell growth of U937 cells were connected with a marked inhibition of cyclin B1 and an induction of Cdk inhibitor p21 proteins by p53-independent manner. These data suggest that genistein may exert a strong anticancer effect and additional studies will be needed to evaluate the different mechanisms between T24 and U937 cells.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.71.1-71.1
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• 2003

We show that Cdc6, an essential initiation factor for DNA replication, undergoes caspase-3-mediated cleavage in the early stages of apoptosis in HeLa cells and SK-HEP-1 cells induced by etoposide, paclitaxel, ginsenoside Rh2, or TRAIL. The cleavage occurs at the SEVD$\^$442//G motif and generates an N-terminal truncated Cdc6 fragment (p49-tCdc6) that lacks the carboxy-terminal nuclear export sequence (NES). Cdc6 is known to be phosphorylated by cyclin A-Cyclin A-dependent kinase 2 (Cdk2), an event that promotes its exit from the nucleus and probably blocks it from initiating inappropriate DNA replication. (omitted)