• Proceedings of the PSK Conference
• /
• 2003.10b
• /
• pp.187.2-187.2
• /
• 2003

The cyclin-dependent kinases (CDKs), a group of serine/threonine kinases that form active heterodimeric complexes binding to cyclins, are key regulators of the cell cycle. The role of cyclin dependent kinases(CDKs) in cell cycle regulation has stimulated an interest in them as potential targets for proliferative diseases such as cancer, psoriasis, and chemotherapeutic agent-induced alopecia. Indirubin, an active ingredient of a traditional Chinese recipe Danggui Longhui Wan, are potent CDK inhibitors competing with ATP for binding to the catalytic site of the CDKs. (omitted)

• Journal of Life Science
• /
• v.11 no.4
• /
• pp.362-370
• /
• 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.

• Molecules and Cells
• /
• v.28 no.1
• /
• pp.37-42
• /
• 2009

Iron binding lactoferrin (Lf) is involved in the control of cell cycle progression. However, the molecular basis underlying the effects of Lf on cell cycle control, as well as its target genes, remains incompletely understood. In this study, we have demonstrated that a relatively low level of ironsaturated Lf, Lf($Fe^{3+}$), can stimulate S phase cell cycle entry, and requires Akt activation in MCF-7 cells. Lf($Fe^{3+}$) immediately induced Akt phosphorylation at Ser473, which subsequently induced the phosphorylation of two G1-checkpoint Cdk inhibitors, $p21^{Cip/WAF1}$ and $p27^{kip1}$. The Lf($Fe^{3+}$)-induced phosphorylation of Cdk inhibitors impaired their nuclear import behavior, thereby inducing cell cycle progression. However, the treatment of cells with a PI3K inhibitor, LY294002, almost completely blocked Lf($Fe^{3+}$)-stimulated cell cycle progression. LY294002 treatment abrogated Lf($Fe^{3+}$)-induced Akt activation, and prevented the cytoplasmic localization of $p27^{kip1}$. Higher levels of $p21^{Cip/WAF1}$ were also detected in the cytoplasmic sub-cellular compartment as a measure of cellular response to Lf($Fe^{3+}$). Consequently, the degree of phosphorylation of retinoblastoma protein was enhanced in response to Lf($Fe^{3+}$). Therefore, we conclude that Lf($Fe^{3+}$), as a potential antagonist of Cdk inhibitors, can facilitate the functions of E2F during progression to S phase via the Akt signaling pathway.

• Journal of Physiology & Pathology in Korean Medicine
• /
• v.22 no.5
• /
• pp.1250-1255
• /
• 2008

Onchungeum(OCE), a herbal formula, has been used for treatment of anemia, discharging blood and skin diseases. In the previous study, we investigated the anti-cancer effect of OCE by G1 arrest of the cell cycle in human hepatocarcinoma cells, Hep3B cells. In this study, it was examined that the difference of anti-proliferative mechanisms by change in the ratio of OCE composition (OCE I) in Hep3B cells. Treatment of OCE I exhibited a relatively strong anti-proliferative activity and caused various morphological changes such as membrane shrinkage and cell floating. In addition, OCE-I arrests the cell cycle at G1 phase, which was associated with the down-regulation of cyclin D1 and Cdk6 expressions. The G1 arrest was also associated with the induction of Cdk inhibitors p27 and p21. Moreover, both p21 and p27 were detected by immunoprecipitation with anti-Cdk4 and anti-Cdk2 antibodies in OCE I-treated cells but in case of OCE, p21 did not make any complexes with Cdk4 and Cdk2. These results suggest that the change in the ratio of OCE composition might induce different mechanisms in anti-cancer efficacy of OCE, which may confer characteristic principles in oriental medical formula.

• 한국약용작물학회:학술대회논문집
• /
• 2006.04a
• /
• pp.93-105
• /
• 2006

P25/CDK5 phosphorylates BACE1. 2. P25 is a new target for AD therapeutics. 3. P25 inhibitors should block both $A{\beta}$ pathway and Tau pathway.

• Journal of Physiology & Pathology in Korean Medicine
• /
• v.20 no.6
• /
• pp.1530-1537
• /
• 2006

Platycodi Radix, the root of Platycodon grandiflorum A. DC (Campanulaceae), commonly known as Doraji in Korea (Chinese name, 'Jiegeng', and Japanese name, 'Kikyo') has been used as an expectorant in traditional Oriental medicine. Extracts from the roots of P. grandiflorum have been reported to have wide ranging health benefits. In Korea, Platycodi Radix is also used as a food and employed as a folk remedy for adult diseases, such as bronchitis, asthma and pulmonary tuberculosis, hyperlipidemia, diabetes, and inflammatory diseases, and as a sedative. Several studies on its chemical and immunopharmacological effects including immunostimulation and antitumor activity have been performed. However, the relevant molecular mechanisms are poorly understood. Platycodi Radix, the root of Platycodon grandiflorum A. DC (Campanulaceae), commonly known as Doraji in Korea (Chinese name, 'Jiegeng', and Japanese name, 'Kikyo') has been used as an expectorant in traditional Oriental medicine. Extracts from the roots of P. grandiflorum have been reported to have wide ranging health bensfits. In Korea, Platycodi Radix is also used as a food and employed as a folk remedy for adult diseases, such as bronchitis, asthma and pulmonary tuberculosis, hyperlipidemia, diabetes, and inflammatory diseases, and as a sedative. Several studies on its chemical and immunopharmacological effects including immunostimulation and antitumor activity have been performed. However, the relevant molecular mechanisms are poorly understood. In the present study, we investigated the effects of an aqueous extract from the roots of P. grandiflorum AEPG) on the cell growth of human lung adenocarcinoma NCI-H460 cells in order to understand its anti-proliferative mechanism. AEPG treatment down-regulated the cyclin D1 expression in both transcriptional and translational levels without alteration of cyclin E. In AEPG-treated cells, the levels of cyclin-dependent kinase (C아) 6 mRNA and protein were significantly inhibited, but the levels of Cdk2 and Cdk4 were slightly inhibited by treatment of AEPG. AEPG treatment induced a marked accumulation of Cdk inhibitors, p16 and p27. However, AEPG treatment did not affect not only retinoblastoma protein (pRB) but also tumor suppressor p53 protein expression. The present results indicated that AEPG-induced inhibition of lung cancer cell proliferation is associated with the blockage of G1 phase progression through induction of Cdk inhibitors such as p16 and p27, and inhibition of cyclin D1 and Cdk6. AEPG exposure, as offered by this study, provides cluse for the mechanism of AEPG action. Taken together, these findings suggest that P. grandiflorum has strong potential for development as an agent for prevention and treatiment against human lung cancer.

• Journal of Microbiology and Biotechnology
• /
• v.32 no.10
• /
• pp.1262-1274
• /
• 2022

Cholangiocarcinoma (CCA) is a complex and refractor type of cancer with global prevalence. Several barriers remain in CCA diagnosis, treatment, and prognosis. Therefore, exploring more biomarkers and therapeutic drugs for CCA management is necessary. CCA gene expression data was downloaded from the TCGA and GEO databases. KEGG enrichment, GO analysis, and protein-protein interaction network were used for hub gene identification. miRNA were predicted using Targetscan and validated according to several GEO databases. The relative RNA and miRNA expression levels and prognostic information were obtained from the GEPIA. The candidate drug was screened using pharmacophore-based virtual screening and validated by molecular modeling and through several in vitro studies. 301 differentially expressed genes (DEGs) were screened out. Complement and coagulation cascades-related genes (including AHSG, F2, TTR, and KNG1), and cell cycle-related genes (including CDK1, CCNB1, and KIAA0101) were considered as the hub genes in CCA progression. AHSG, F2, TTR, and KNG1 were found to be significantly decreased and the eight predicted miRNA targeting AHSG, F2, and TTR were increased in CCA patients. CDK1, CCNB1, and KIAA0101 were found to be significantly abundant in CCA patients. In addition, Molport-003-703-800, which is a compound that is derived from pharmacophores-based virtual screening, could directly bind to CDK1 and exhibited anti-tumor activity in cholangiocarcinoma cells. AHSG, F2, TTR, and KNG1 could be novel biomarkers for CCA. Molport-003-703-800 targets CDK1 and work as potential cell cycle inhibitors, thereby having potential for consideration for new chemotherapeutics for CCA.

• Bulletin of the Korean Chemical Society
• /
• v.26 no.12
• /
• pp.2065-2068
• /
• 2005

• Environmental Mutagens and Carcinogens
• /
• v.25 no.3
• /
• pp.87-96
• /
• 2005

[ $p16^{INK4a}$ ] is a tumor suppressor that belongs to the INK4 family of the cyclin D-dependent kinases (cdk) inhibitors. It plays regulatory roles in cell proliferation and in tumorigenesis by interacting with Rb signaling. Abnormally elevated $p16^{INK4a}$ protein expression causes cell cycle arrest (G1/S transition) and loss of cyclin-cdk activity. In many cancers, $p16^{INK4a}$ is altered by mutation, deletion, and promoter methylation. This review summarizes the function of p16 as an important regulator of cancer pathobiology and a promising target fer developing cancer therapeutic and chemopreventive agents.

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