scholarly journals Induction of cell cycle arrest via the p21, p27–cyclin E,A/Cdk2 pathway in SMMC-7721 hepatoma cells by clioquinol

2015 ◽  
Vol 65 (4) ◽  
pp. 463-471 ◽  
Author(s):  
Zhiwei Huang ◽  
Lianqiu Wang ◽  
Lifeng Chen ◽  
Yifei Zhang ◽  
Ping Shi
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Cycle Progression ◽  
Therapeutic Potential ◽  
Cyclin E ◽  
S Phase ◽  
Dependent Manner ◽  
Hepatic Cells ◽  
Cycle Arrest ◽  
First Time

Abstract Clioquinol has been shown to have anticancer activity in several carcinoma cells. In this study, we preliminarily examined the effect of clioquinol in human SMMC-7721 hepatoma and QSG-7701 normal hepatic cells. Our results indicated that clioquinol did not significantly affect survival of QSG-7701 cells, whereas it reduced cell viability in a concentration- and time-dependent manner in SMMC-7721 cells. Clioquinol did not trigger autophagy and apoptosis, while it induced cell cycle arrest in the S-phase in SMMC- 7721 cells. Additionally, down-regulation of cyclin D1, A2, E1, Cdk2 and up-regulation of p21, p27 were detected after the treatment with clioquinol. The results demonstrated for the first time that clioquinol suppressed cell cycle progression in the S-phase in SMMC-7721 cells via the p21, p27-cyclin E,A/Cdk2 pathway. This suggests that clioquinol may have a therapeutic potential as an anticancer drug for certain malignances.

scholarly journals The Cyclin E/Cdk2 Substrate p220NPAT Is Required for S-Phase Entry, Histone Gene Expression, and Cajal Body Maintenance in Human Somatic Cells

2003 ◽  
Vol 23 (23) ◽  
pp. 8586-8600 ◽  
Author(s):  
Xin Ye ◽  
Yue Wei ◽  
Grzegorz Nalepa ◽  
J. Wade Harper
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cyclin E ◽  
S Phase ◽  
Cajal Body ◽  
Histone H4 ◽  
Cycle Arrest ◽  
Histone Transcription ◽  
Phase Entry ◽  
Hct116 Cells

ABSTRACT Cyclin E/Cdk2, a central regulator of the G1/S transition, coordinates multiple cell cycle events, including DNA replication, centrosome duplication, and activation of the E2F transcriptional program. Recent studies suggest a role for cyclin E/Cdk2 in activation of histone transcription during S phase via the Cajal body-associated protein p220NPAT, and in addition, p220 can promote S-phase entry independently of histone transcriptional activation when overexpressed. Here we have examined the requirement for p220 in histone transcription, cell cycle progression, and Cajal body function through analysis of human somatic HCT116 cells engineered to contain a conditional p220 allele. p220 is required for proliferation of HCT116 cells, as assessed after expression of Cre recombinase in p220flox/− cells. This defect was due to an inability of these cells to transit from G0/G1 into S phase, and cell cycle arrest occurred in the presence of elevated Cdk2 kinase activity. Expression of human papillomavirus E7, but not E6, eliminated cell cycle arrest in response to p220 depletion. Optimal expression of all four core histone genes required p220, as did optimal transcription of a histone H4 promoter-luciferase construct. Basal histone H4 expression in G0/G1, although p220 dependent, occurs in the absence of detectable phosphorylation of p220 on Cdk2 sites. Cells lacking p220 displayed defects in the localization of the Cajal body component p80coilin as cells progressed from G0 to S phase in response to mitogenic signals. These finding indicate that p220 is an essential downstream component of the cyclin E/Cdk2 signaling pathway and functions to coordinate multiple elements of the G1/S transition.

scholarly journals A β-carboline derivative-based nickel(ii) complex as a potential antitumor agent: synthesis, characterization, and cytotoxicity

MedChemComm ◽  
2018 ◽  
Vol 9 (1) ◽  
pp. 100-107 ◽  
Author(s):  
Jing-Mei Yang ◽  
Yan-Hong Zhu ◽  
Sheng Chen ◽  
Xing Lu ◽  
Yi-Ming Wu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cyclin E ◽  
Antitumor Agent ◽  
Cyclin A ◽  
S Phase ◽  
Down Regulation ◽  
Cycle Arrest ◽  
Potential Antitumor

A novel nickel(ii) complex was synthesized and characterized. It significantly induced cell cycle arrest at S phase, and caused the down-regulation of p-AKT, cyclin E, cyclin A and CDK2 and the up-regulation of p27.

scholarly journals Resveratrol Induces Cell Cycle Arrest and Apoptosis in Malignant NK Cells Via JAK2/STAT3 Pathway Inhibition

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1343-1343 ◽  
Author(s):  
Ly Quoc Trung ◽  
Luis Jorge Espinoza ◽  
Akiyoshi Takami ◽  
Akiyo Yoshida ◽  
Shinji Nakao
Keyword(s):  
Cell Cycle ◽  
Nk Cells ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Intracellular Signaling ◽  
Nk Cell ◽  
Therapeutic Potential ◽  
Dependent Manner ◽  
Stat3 Pathway ◽  
Cycle Arrest

Abstract Abstract 1343 Natural killer (NK)-cell malignancies, particularly aggressive NK-cell leukemias/lymphomas, have poor prognoses. Although recent regimens that include L-asparaginase substantially improve outcomes, novel therapeutic approaches are needed to improve clinical responses. Recent reports have shown that the signal transducer and activator of transcription 3 (STAT3) pathway is critical for proliferation and survival of malignant NK cells. Resveratrol is a naturally-occurring polyphenol that has been extensively studied for its anti-inflammatory, cardioprotective, and anti-cancer activities. In this study, we investigated the potential anti-tumor activities of resveratrol against the NK cell lines KHYG-1, NKL, NK-92, and NK-YS. Resveratrol significantly suppressed cell proliferation in a dose- and time-dependent manner in these four cell lines. Flow cytometry analysis with annexin V/propidium iodide staining showed a variable but consistent induction of apoptosis in the four cell lines treated with resveratrol for 48 hours, ranging from 57.1±6.9% of apoptosis in the L-asparaginase resistant cell line KHYG-1 to 53.4±9.7%, 28.8±3.3%, and 51.7±6.7% in NKL, NK-92, and NK-YS cells respectively (Fig. 1a). Notably, the anti-tumor activity of resveratrol against NK cell lines was p53 independent as demonstrated by equal efficacy of resveratrol against NK cell lines pretreated with the p53 inhibitor Pifithrin-α. Immunoblot analysis to study intracellular signaling in resveratrol-treated cells showed suppression of constitutively active STAT3 in all four cell lines 24 hours after treatment. Remarkably, resveratrol inhibited JAK2 phosphorylation, but had no effect on other known upstream mediators of STAT3 activation such as PTEN and Tyk2 (Fig. 1b). Resveratrol induced robust G1 cell cycle arrest and down-regulation of two anti-apoptotic proteins, Mcl-1 and survivin, both of which are downstream effectors of the STAT-3 pathway. Furthermore, resveratrol enhanced the pro-apoptotic and anti-proliferative activities of L-asparaginase against NKL and NK-92 cells by 32% and 126% respectively. These data indicate that resveratrol possesses a potent anti-tumor effect via inactivation of the STAT3 pathway in malignant NK cells. These mechanistic findings suggest that resveratrol may have therapeutic potential against NK cell malignancies. Our finding that resveratrol is a bonafide JAK2 inhibitor extends its therapeutic potential to other diseases with deregulated JAK2 signaling. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1.

1997 ◽  
Vol 17 (9) ◽  
pp. 5598-5611 ◽  
Author(s):  
D Woods ◽  
D Parry ◽  
H Cherwinski ◽  
E Bosch ◽  
E Lees ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Cell Cycle Arrest ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Cyclin E ◽  
G1 Arrest ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
Primary Mouse

The Raf family of protein kinases display differences in their abilities to promote the entry of quiescent NIH 3T3 cells into the S phase of the cell cycle. Although conditional activation of deltaA-Raf:ER promoted cell cycle progression, activation of deltaRaf-1:ER and deltaB-Raf:ER elicited a G1 arrest that was not overcome by exogenously added growth factors. Activation of all three deltaRaf:ER kinases led to elevated expression of cyclin D1 and cyclin E and reduced expression of p27Kip1. However, activation of deltaB-Raf:ER and deltaRaf-1:ER induced the expression of p21Cip1, whereas activation of deltaA-Raf:ER did not. A catalytically potentiated form of deltaA-Raf:ER, generated by point mutation, strongly induced p21Cip1 expression and elicited cell cycle arrest similarly to deltaB-Raf:ER and deltaRaf-1:ER. These data suggested that the strength and duration of signaling by Raf kinases might influence the biological outcome of activation of this pathway. By titration of deltaB-Raf:ER activity we demonstrated that low levels of Raf activity led to activation of cyclin D1-cdk4 and cyclin E-cdk2 complexes and to cell cycle progression whereas higher Raf activity elicited cell cycle arrest correlating with p21Cip1 induction and inhibition of cyclin-cdk activity. Using green fluorescent protein-tagged forms of deltaRaf-1:ER in primary mouse embryo fibroblasts (MEFs) we demonstrated that p21Cip1 was induced by Raf in a p53-independent manner, leading to cell cycle arrest. By contrast, activation of Raf in p21Cip1(-/-) MEFs led to a robust mitogenic response that was similar to that observed in response to platelet-derived growth factor. These data indicate that, depending on the level of kinase activity, Raf can elicit either cell cycle progression or cell cycle arrest in mouse fibroblasts. The ability of Raf to elicit cell cycle arrest is strongly associated with its ability to induce the expression of the cyclin-dependent kinase inhibitor p21Cip1 in a manner that bears analogy to alpha-factor arrest in Saccharomyces cerevisiae. These data are consistent with a role for Raf kinases in both proliferation and differentiation of mammalian cells.

scholarly journals The RASSF1A Tumor Suppressor Blocks Cell Cycle Progression and Inhibits Cyclin D1 Accumulation

2002 ◽  
Vol 22 (12) ◽  
pp. 4309-4318 ◽  
Author(s):  
Latha Shivakumar ◽  
John Minna ◽  
Toshiyuki Sakamaki ◽  
Richard Pestell ◽  
Michael A. White
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cyclin D1 ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Phase Cell ◽  
Cycle Progression ◽  
Cycle Arrest

ABSTRACT The RASSF1A locus at 3p21.3 is epigenetically inactivated at high frequency in a variety of solid tumors. Expression of RASSF1A is sufficient to revert the tumorigenicity of human cancer cell lines. We show here that RASSF1A can induce cell cycle arrest by engaging the Rb family cell cycle checkpoint. RASSF1A inhibits accumulation of native cyclin D1, and the RASSF1A-induced cell cycle arrest can be relieved by ectopic expression of cyclin D1 or of other downstream activators of the G1/S-phase transition (cyclin A and E7). Regulation of cyclin D1 is responsive to native RASSF1A activity, because RNA interference-mediated downregulation of endogenous RASSF1A expression in human epithelial cells results in abnormal accumulation of cyclin D1 protein. Inhibition of cyclin D1 by RASSF1A occurs posttranscriptionally and is likely at the level of translational control. Rare alleles of RASSF1A, isolated from tumor cell lines, encode proteins that fail to block cyclin D1 accumulation and cell cycle progression. These results strongly suggest that RASSF1A is an important human tumor suppressor protein acting at the level of G1/S-phase cell cycle progression.

scholarly journals Legionella pneumophila translocated translation inhibitors are required for bacterial-induced host cell cycle arrest

2018 ◽  
Author(s):  
Asaf Sol ◽  
Erion Lipo ◽  
Dennise A. de Jesús ◽  
Connor Murphy ◽  
Mildred Devereux ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Host Cell ◽  
Legionella Pneumophila ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
Bacterial Replication ◽  
Cell Cycle Machinery

AbstractThe cell cycle machinery controls diverse cellular pathways and is tightly regulated. Misregulation of cell division plays a central role in the pathogenesis of many disease processes. Various microbial pathogens interfere with the cell cycle machinery to promote host cell colonization. Although cell cycle modulation is a common theme among pathogens, the role that this interference plays in promoting diseases is unclear. Previously we demonstrated that the G1 and G2/M phases of the host cell cycle are permissive for Legionella pneumophila replication, while S phase provides a toxic environment for bacterial replication. In this study we show that L. pneumophila avoids host S phase by blocking host DNA synthesis and preventing cell cycle progression into S phase. Cell cycle arrest upon Legionella contact is dependent on the Icm/Dot secretion system. In particular, we found that cell cycle arrest is dependent on the intact enzymatic activity of translocated substrates that inhibits host translation. Moreover, we show that early in infection, the presence of these translation inhibitors is crucial to induce the degradation of the master regulator cyclin D1. Our results demonstrate that the bacterial effectors that inhibit translation are associated with preventing entry of host cells into a phase associated with restriction of L. pneumophila. Furthermore, control of cyclin D1 may be a common strategy used by intracellular pathogens to manipulate the host cell cycle and promote bacterial replication.SignificanceRecently, we showed that host cell cycle regulatory proteins control L. pneumophila growth. In particular, bacterial replication was found to be depressed in S-phase. This indicates that bacterial control of the host cell cycle can limit exposure of the pathogen to antimicrobial events that are cycle-specific. Here we uncovered bacterial factors that induce host cell cycle arrest by inhibiting host protein synthesis and preventing S phase transition. These data are consistent with S-phase toxicity serving as an important antimicrobial response that limits growth of some intracellular pathogens. Moreover, identification of microbial factors that block cell cycle progression and uncovering host cell cycle partners are candidates for future drug development. Our data point to a unifying role of the cell cycle in multiple disease processes.

Rhein Induces Apoptosis and Cell Cycle Arrest in Human Hepatocellular Carcinoma BEL-7402 Cells

2008 ◽  
Vol 36 (04) ◽  
pp. 805-813 ◽  
Author(s):  
Ping Shi ◽  
Zhiwei Huang ◽  
Guichen Chen
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Chromatin Condensation ◽  
Critical Role ◽  
S Phase ◽  
Dependent Manner ◽  
Hepatocelluar Carcinoma ◽  
Cycle Arrest ◽  
Phase Arrest ◽  
S Phase Arrest

Rhein, an anthraquinone derivative of rhubarb, inhibits the proliferation of various human cancer cells. In this paper, we focused on studying the effects of rhein on human hepatocelluar carcinoma BEL-7402 cells and further understanding the underlying molecular mechanism in an effort to make the potential development of rhein in the treatment of cancers. Using MTT assay and flow cytometry, we demonstrate a critical role of rhein in the suppression of BEL-7402 cell proliferation in a concentration- and time-dependent manner. The increase of apoptosis rate was observed after incubation of BEL-7402 cells with rhein at 50–200 μM for 48 hours, and the cells exhibit typical apoptotic features including cellular morphological change and chromatin condensation. Moreover, rhein-induced cell cycle S-phase arrest. Additionally, after rhein treatment, expression levels of c-Myc gene were decreased, while those of caspase-3 gene were increased in a dose-dependent manner by using real-time PCR assay. The results demonstrate for the first time that cell cycle S-phase arrest is one of the mechanisms of rhein in inhibition of BEL-7402 cells. Rhein plays its role by inducing cell cycle arrest via downregulation of oncogene c-Myc and apoptosis through the caspase-dependent pathway. It is expected that rhein will be effective and useful as a new agent in hepatocelluar carcinoma treatment in the future.

scholarly journals Murine Coronavirus Nonstructural Protein p28 Arrests Cell Cycle in G0/G1 Phase

2004 ◽  
Vol 78 (19) ◽  
pp. 10410-10419 ◽  
Author(s):  
Chun-Jen Chen ◽  
Kazuo Sugiyama ◽  
Hideyuki Kubo ◽  
Cheng Huang ◽  
Shinji Makino
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cell Cycle Progression ◽  
Hepatitis Virus ◽  
Nonstructural Protein ◽  
Dependent Manner ◽  
Nonstructural Proteins ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
Murine Coronavirus

ABSTRACT Murine coronavirus mouse hepatitis virus (MHV) gene 1 encodes several nonstructural proteins. The functions are unknown for most of these nonstructural proteins, including p28, which is encoded at the 5′ end of the MHV genome. Transient expression of cloned p28 in several different cultured cells inhibited cell growth, indicating that p28 expression suppressed cell proliferation. Expressed p28 was exclusively localized in the cytoplasm. Cell cycle analysis by flow cytometry demonstrated that p28 expression induced G0/G1 cell cycle arrest. Characterization of various cellular proteins that are involved in regulating cell cycle progression demonstrated that p28 expression resulted in an accumulation of hypophosphorylated retinoblastoma protein (pRb), tumor suppressor p53, and cyclin-dependent kinase (Cdk) inhibitor p21Cip1. Expression of p28 did not alter the amount of p53 transcripts yet increased the amount of p21Cip1 transcripts, suggesting that p28 expression increased p53 stability and that p21Cip1 was transcriptionally activated in a p53-dependent manner. Our present data suggest the following model of p28-induced G0/G1 cell cycle arrest. Expressed cytoplasmic p28 induces the stabilization of p53, and accumulated p53 causes transcriptional upregulation of p21Cip1. The increased amount of p21Cip1 suppresses cyclin E/Cdk2 activity, resulting in the inhibition of pRb hyperphosphorylation. Accumulation of hypophosphorylated pRb thus prevents cell cycle progression from G0/G1 to S phase.

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