G1细胞周期调控因子与肿瘤

细胞周期调控是指各种调控因子在细胞周期检测点的控制下通过自身的激活和灭活,使细胞启动和完成细胞周期重要事件,并保障这些事件按次序正常进行。细胞周期调控因子包括正凋控因子细胞周期蛋白(Cyclins)、细胞周期蛋白依赖性蛋白激酶(CDK)及负凋控因子细胞周期蛋白依赖性蛋白激酶抑制剂(CDIs)。细胞周期正调控因子的过度表达、异常活跃及负调控因子的表达缺失以及检测点的异常而导致细胞周期紊乱而致癌。     

细胞周期调控基因与妇科恶性肿瘤

肿瘤细胞的基本特征是细胞生长失控和分化受阻。细胞生长和分化的调节与细胞周期中的诸多因素密切相关 ,因而出现了“癌症可能是一类细胞周期疾病”的观点［１］。与细胞周期调节有关的分子有三类 :细胞周期蛋白（ｃｙｃｌｉｎ）、细胞周期蛋白依赖性激酶（ｃｙｃｌｉｎ ｄｅｐｅｎｄｅｎｔｋｉｎａｓｅ ,ＣＤＫ）、细胞周期蛋白依赖性激酶抑制蛋白（ｃｙｃｌｉｎ ｄｅｐｅｎｄｅｎｔｋｉｎａｓｅｉｎ ｈｉｂｉｔｏｒ,ＣＫＩ） ,这三类分子共同构成了细胞周期的网络调控系统ｃｙｘｌｉｎｓ ＣＤＫｓ ＣＫＩｓ,这一系统中的调节基因及蛋白的…     

细胞周期调控基因与妇科恶性肿瘤

肿瘤细胞的基本特征是细胞生长失控和分化受阻.细胞生长和分化的调节与细胞周期中的诸多因素密切相关,因而出现了"癌症可能是一类细胞周期疾病"的观点[1].与细胞周期调节有关的分子有三类:细胞周期蛋白(cyclin)、细胞周期蛋白依赖性激酶(cyclin-dependent kinase,CDK)、细胞周期蛋白依赖性激酶抑制蛋白(cyclin-dependent kinase inhibitor,CKI),这三类分子共同构成了细胞周期的网络调控系统cyxlins-CDKs-CKIs,这一系统中的调节基因及蛋白的改变和肿瘤发生、发展、治疗以及预后的关系,是目前国内外肿瘤研究的热点.本文就细胞周期的调节基因在妇科恶性肿瘤中的研究进展做一简要阐述.     

胃癌细胞周期蛋白B_1过度表达

细胞周期蛋白Ｂ１（ＣｙｃｌｉｎＢ１）是细胞周期中Ｇ２／Ｍ期转换过程中的关键调节蛋白。虽然细胞周期蛋白Ｂ１ 在各种类型的人癌中都是过度表达 ,但细胞周期蛋白Ｂ１ 在胃癌的情况及其临床意义之间的关系还是不明确的。日本福冈齿科大学医院普外科ＹａｓｕｄａＭ等用免疫组化方法检测６１例胃癌病人细胞周期蛋白Ｂ１ 的表达 ,并结合其组织学类型、肿瘤浸润和转移行为进行分析。把１０%以上癌细胞群的胞浆着色确定为阳性。结果 :细胞周期蛋白Ｂ１ 在５３%的胃癌病人过度表达（３２／６１） ,周期蛋白Ｂ１ 过度表达主要是在年老的病人、高…     

活性氧调控细胞增殖的分子机制研究进展

细胞增殖是生命的基本特征,而异常细胞增殖是肿瘤等增殖相关疾病的发病基础。细胞增殖取决于细胞周期,低剂量的活性氧(ROS)具有信号转导和促进细胞增殖作用,这种作用是通过影响细胞周期检测点、细胞周期蛋白、细胞周期蛋白依赖性激酶(CDKs)、细胞周期蛋白依赖性激酶抑制剂(CKIs)、泛素蛋白酶体等机制实现的。ROS通过抑制CKIs活性和泛素化作用,升高cyclinCDK活性,加速细胞通过周期检测点。最终细胞周期时间缩短,表现为ROS的促细胞增殖效应。     

中药影响乳腺癌细胞周期的研究进展

0引言早在20世纪90年代,已有学者提出肿瘤是一种细胞周期疾病,细胞周期调节紊乱是肿瘤发生的重要环节[1].乳腺癌是女性最常见的恶性肿瘤之一,乳腺癌的发生发展与细胞周期调控因子表达异常密切相关[2].细胞的生命开始于细胞周期,细胞周期的正常运行依赖于精细的调控机制,细胞周期蛋白(cycline)、细胞周期蛋白依赖性激酶(cyclin depengdent kinase,CDK)、细胞周期蛋白依赖性激酶抑制剂(cyclin dependent kinase inhibitor,CKI)三者相互作用,共同参与细胞周期调控,在维持细胞有序的增殖、分裂活动中起重要作用[3,4].     

非小细胞肺癌中细胞周期蛋白D1与E的作用及相互关系

目的 :研究细胞周期蛋白D1与E在非小细胞肺癌 (NSCLC)发生、发展中的作用及相互关系。方法 :免疫组化方法检测 87例NSCLC肿瘤组织中细胞周期蛋白D1、E的表达及PCNA估计增殖指数 (PI) ,并将上述结果与临床病理及预后资料进行对比分析。结果 :87例NSCLC中细胞周期蛋白D1、E阳性率分别为 4 4 .8% (39/87)、4 8.3% (42 /87) ,细胞周期蛋白D1阳性组的PI值显著高于阴性组 (P〈0 .0 5 ) ,细胞周期蛋白E阳性组PI值与阴性组无显著差异 (P〉0 .0 5 ) ;细胞周期蛋白D1阳性组肿瘤直径、淋巴结转移率和生存率均与阴性组有显著差异(P〈0 .0 1、〈0 .0 5、〈0 .0 1) ,细胞周期蛋白E阳性组淋巴结转移率、临床分期和生存率均与阴性组有显著差异 (P〈0 .0 5、〈0 .0 5、〈0 .0 1) ;细胞周期蛋白D1阳性组中细胞周期蛋白E的阳性率显著高于其阴性组 (P〈0 .0 5 ) ;细胞周期蛋白D1与细胞周期蛋白E双阳性组的PI值、肿瘤直径、淋巴结转移率显著高于非双阳性组 (P值均〈0 .0 5 ) ,生存率显著低于非双阳性组 (P〈0 .0 1)。结论 :细胞周期蛋白D1、细胞周期蛋白E均参与NSCLC的发生、发展 ,并影响其预后 ,但两者在其中所起作用不同 :细胞周期蛋白D1是调节NSCLC增殖的主要因素 ,细胞周期蛋白E主要与NSCLC进展有关 ;细胞周期蛋白D1可促     

细胞周期蛋白依赖性激酶与肿瘤关系的研究进展

在生物进化过程中,细胞发展并建立了一系列的精细的调控机制,以确保细胞周期严格有序地交替和各时相依次有序变更。细胞周期蛋白依赖性激酶（CDKs）是细胞周期调节的核心,其与细胞周期蛋白（Cyclins）、细胞周期蛋白依赖性激酶抑制因子（CKIs）等组成细胞周期调控网络系统。早在90年代,人们就提出肿瘤是一种细胞周期疾病,细胞周期中任一环节的抗过度增生的调控机制发生改变,则导致肿瘤的发生。了解CDKs在细胞周期调控中的作用及与肿瘤的关系对认识肿瘤发生和演进、临床诊断及治疗有十分重要的意义。     

cyclin D1基因异常表达、多态性与乳腺癌关系

对细胞周期调控机制的研究表明,细胞周期蛋白(cyclin)是细胞周期中短暂出现的基因表达产物,具有严格的顺序性,与特定的细胞周期蛋白依赖性激酶(CDK)结合构成复合体,使CDK活化,完成各个时相的转换,然后降解。目前认为在细胞周期的     

抑癌基因p16与细胞周期调控

细胞周期是细胞生命活动的基本过程,细胞在周期时相的变迁中进入增殖、分化、衰老和死亡等生理状态。若细胞周期调控异常,细胞将进入病理状态,且与肿瘤的发生也密切相关。参与细胞周期调控的分子主要包括:细胞周期蛋白(cyclin),细胞周期蛋白依赖性激酶(cy-clin-dependentkinase,CDK),磷酸化酶以及细胞周期蛋白依赖性激酶抑制蛋白(CDKinhibitorCKI),这些调节成分组成多条调节途径,通过使Rb磷酸化或去磷酸化构成以Rb为中心的一个复杂网络[1]。CKI通过竞争性结合cyclin或CDK/cyclin复合物,导致cyclin生物活性丧失,最终表现为负调控细胞…     

HOTAIR,a long noncoding RNA,is a marker of abnormal cell cycle regulation in lung cancer

Dysregulation of the cell cycle is a key indicator of tumors, including lung cancer. Recently, the study of cell cycle inhibitors has made great progress in relation to lung cancer. However, the question of what kinds of patients can use cell cycle inhibitors has plagued us. Therefore, seeking an accurate and convenient marker for the abnormal cell cycle in lung cancer is very important. In the present research, we showed that lncRNA HOTAIR is an optimal indicator of cell cycle dysregulation in lung cancer. In the present study, we investigated HOTAIR‐specific expression in lung primary tumor samples by analyzing the TCGA public database and 67 pairs of patients’ tissues collected from our department. Through the TCGA public database KEGG analysis, HOTAIR correlates with the cell cycle pathway. We identified that HOTAIR and its 2 segments, HOTAIR3′ and HOTAIR5′, promote the cell cycle passing through the restriction point during G1‐S phase by regulating the Rb‐E2F pathway and influence non–small‐cell lung cancer cell proliferation, migration and invasion through epithelial‐mesenchymal transition (EMT) and the β‐catenin pathway in vitro and vivo. Finally, we showed that the high expression of HOTAIR was associated with resistance to gefitinib through the dysregulated cell cycle. In conclusion, HOTAIR could be an ideal indicator of cell cycle dysregulation and guide the use of cell cycle inhibitors.     

中药对肿瘤细胞周期影响的研究进展

每一个生命个体中, 都存在一个决定细胞是否、何时开始生长、分裂或死亡的精密程序, 即细胞周期调控机制, 其在相关基因的控制下, 调控细胞的生长、分裂和死亡。细胞周期调控机制的破坏导致细胞的失控性生长, 是几乎所有的肿瘤都有的一个根本的共同特征。许多癌基因、抑癌基因突变的结果是改变了细胞周期的调控, 包括细胞周期启动、运行和终止的异常, 使本来应脱离细胞周期而停止增殖或应自行凋亡的细胞不断地进入细胞周期, 从而出现无限制、自主的细胞增殖和分裂。传统中草药用于治疗癌症有着悠久的历史, 中药因其资源丰富且副反应较小, 在抗肿瘤药物的筛选上备受关注, 许多中药或其有效成分可阻滞肿瘤细胞周期于G₁期、S期或G₂/M期, 抑制癌细胞增殖, 并诱导凋亡, 从而发挥抗肿瘤作用。本文将中药对肿瘤细胞周期的影响及机制做一综述。      

PI3K class IB controls the cell cycle checkpoint promoting cell proliferation in hepatocellular carcinoma

Alterations of the cell cycle checkpoint frequently occur during hepatocarcinogenesis. Dysregulation of the phosphatidylinositol-3-kinases (PI3K) signaling pathway is believed to exert a potential oncogenic effect in hepatocellular carcinoma (HCC), ultimately promoting tumor cell proliferation. However, the impact of PI3K on cell cycle regulation remains unclear. We used a combined loss- and gain-of-function approach to address the involvement of p110γ in HCC cell proliferation, apoptosis and the cell cycle. We also investigated the correlation between p110γ and Ki-67 in 24 HCC patients. Finally, we analyzed the expression levels of p110γ and cell cycle regulators in HCC tissues. We found that PI3K class IB, but not class IA, is required for HCC cell proliferation. In particular, we found that knock-down of p110γ inhibits cell proliferation because of an arrest of the cell cycle in the G0-G1 phase. This effect is associated with an altered expression of proteins regulating the cell cycle progression, including p21, and with an increased apoptosis. By contrast, we found that ectopic expression of p110γ promotes HCC cell proliferation. Tissues analysis performed in HCC patients showed a positive correlation between the expression of p110γ and Ki-67, a marker of proliferation, and, even more importantly, that p21 expression is up-regulated in HCC patients with a lower p110γ expression. Our results emphasize the role of p110γ as a promoter of HCC proliferation and unveil an important cell cycle regulation function of this molecule.     

Prevention of entrance into G2 cell cycle phase by mimosine decreases locomotion of cells from the tumor cell line SW480

Cellular proliferation of tumor cells is thought to impede migratory activity. Using continuous single cell migration analysis of the colon carcinoma cell line SW480 for up to 72 h, we were able to show that cells locomote constantly and stop only for actual cell division. These findings indicate that proliferation (from G₁ phase to early mitosis) and migration do occur simultaneously. The presence of the cell cycle marker Ki-67 in individual migrating cells substantiated this observation. Inhibition of cell cycle progression by mimosine (MIM), a reversible cell cycle blocker, reduced the percentage of migrating cells; release from MIM block restored migratory capacity. The corresponding cell cycle phase distributions were confirmed by flow cytometry. In our test system cell cycle events and migration were shown to occur at the same time. Interference with cell cycle progression reduced migratory activity indicating that migration depends on an unhampered cell cycle.     

Calcium/calmodulin-dependent kinase I and calcium/calmodulin-dependent kinase kinase participate in the control of cell cycle progression in MCF-7 human breast cancer cells

Calcium is universally required for cell growth and proliferation. Calmodulin is the main intracellular receptor for calcium. Although calcium and calmodulin are well known to be required for cell cycle regulation, the target pathways for their action remain poorly defined. Potential targets include the calcium/calmodulin-dependent kinases (CaM-K). The aim of this study was to determine the role of the CaM-Ks on cell proliferation and progress through the cell cycle in breast cancer cells. CaM-KI inhibition with either KN-93 or specific interfering RNA (siRNA) caused an arrest in the cell cycle in the human breast cancer cell line, MCF-7. This arrest occurred in the G(1) phase of the cell cycle. Supporting this finding, CaM-K inhibition using KN-93 also resulted in a reduction of cyclin D1 protein and pRb phosphorylation when cells were compared with control cultures. Furthermore, inhibition of the upstream activator of CaM-KI, CaM-KK, using siRNA also resulted in cell cycle arrest. In summary, CaM-KK and CaM-KI participate in the control of the G(0)-G(1) restriction check point of the cell cycle in human breast cancer cells. This arrest seems due to an inhibition in cyclin D1 synthesis and a reduction in pRb phosphorylation. To the best of our knowledge, this is the first time that CaM-KK has been reported to be involved in mammalian cell cycle regulation and that CaM-Ks are regulating breast cancer cell cycle.     

Further mechanistic unravelling of the influence of the cell cycle effects on the radiosensitising mechanism of vinflunine, in vitro

PURPOSE: Vinflunine is an innovative microtubule inhibitor belonging to the vinca alkaloid class that possesses radiosensitising properties, which could lead to promising activity in chemoradiation studies in the clinic. METHOD: In the current study, different incubation times with vinflunine, immediately before radiation and different time intervals between vinflunine treatment and radiation were investigated, in vitro, using four different human tumour cell lines differing in cell type and p53 status. Results were correlated with the cell cycle distribution at the moment of radiation, in order to elucidate the role of cell cycle perturbations caused by vinflunine on its radiosensitising effect. RESULTS: Radiosensitisation was observed in all cell lines, and maximal radiosensitisation was both cell line- and schedule-dependent. The cell cycle distributions were cell line-dependent also, and when correlated with the observed radiosensitising effects could explain many (but not all) of the radiosensitising properties of vinflunine. CONCLUSION: The cell cycle perturbations caused by vinflunine may definitely have an impact on its radiosensitising potential, but other factors must play a role because of some unaccountable differences between cell cycle distribution and the radiosensitising potential.     

Cell cycle arrest and lytic induction of EBV-transformed B lymphoblastoid cells by a histone deacetylase inhibitor, Trichostatin A

Latent infection of the Epstein-Barr virus (EBV) is strongly associated with the pathogenesis of several human tumor types. The restricted expression of the latent EBV antigens is critical for EBV-associated tumors to escape from immune surveillance. EBV lytic replication can be triggered by various treatments and the induced lytic genes cause strong cytotoxic T lymphocyte (CTL) responses. Histone acetylation or deacetylation is associated with chromatin remodeling and regulates gene expression. Histone deacetylase (HDAC) inhibitors affect cell cycle progression as well as gene expression in a wide variety of transformed cells. We examined whether an HDAC inhibitor, TSA, can affect cell cycle progression and induce EBV lytic replication in EBV-transformed lymphoblastoid cell lines (LCLs). TSA caused cell cycle arrest at low concentrations and induced apoptosis at higher (>300 nM) concentrations in the LCLs and EBV negative BJAB cells. To clarify the underlying mechanism of TSA-induced cell cycle arrest, expression of cell cycle regulatory factors was examined by RNase protection assay and Western blot analysis. Following TSA treatment, a reduced expression of cyclin D2 and an induction of p21 may have played an essential role for G1 arrest in LCLs, while p21 induction might have arrested BJAB cells in G1 phase. A Cdk inhibitor, p57, was increased by 300 nM TSA in both LCLs and BJAB cells, indicating its role in apoptosis. Moreover, immunofluorescene assay and Western blotting showed that TSA induced EBV lytic replication in LCL cells. These results suggest that TSA may exert an enhanced anti-tumor effect for EBV-associated tumors not only by inducing a cell cycle arrest and apoptosis, but also by triggering an EBV lytic cycle.     

Analysis of the effects of antitumor drugs on cell cycle kinetics.

A cell cycle stage-specific multicompartmental model has been developed and used to investigate the effects of antitumor drugs on the proliferation of tumors. The drug effects simultaneously considered are (a) non-cycle-specific killing and cycle stage-specific killing of cells, (b) progression delay of cells through the cell cycle phases which may bring about an accumulation of cells in various phases of the cell cycle, and (c) prolongation of cell cycle times. These effects are analyzed in terms of possible variations in the behavior of cell kinetic parameters (namely, cell cycle times, cell loss rate, and growth fraction) and are implemented in the model specifying proper functional forms for the parameters. The time-course of drug distribution in a tumor-host system is also described by a two-compartment model and the factors affecting drug action are quantitatively formulated as a function of drug concentration. Simulation is carried out to examine the effects of BCNU, cytosine arabinoside, and methotrexate on the cell cycle and proliferation kinetics of L1210 leukemia, and the results of the simulation compare favorably with available experimental data. Also discussed are the sensitivity of drug effects to variation in dosage schedule and the different nodes of drug actions exerted on each cell cycle phase.     

Sp1 as G1 cell cycle phase specific transcription factor in epithelial cells

Sp1 binding sites have been identified in enhancer/promoter regions of several growth and cell cycle regulated genes, and it has been shown that Sp1 is increasingly phosphorylated in G1 phase of the cell cycle. Interactions of Sp1 with proteins involved in control of cell cycle and tumor formation have been reported. Here we show that expression of Sp1 protein predominates in the G1 phase of the cell cycle in epithelial cells. This is achieved by proteasome-dependent degradation. Inhibition of endogeneous Sp1 activity by a dominant-negative Sp1 mutant was associated with a cell cycle arrest in G1 phase, a strongly reduced expression of cyclin D1, the EGF-receptor and increased levels of p27Kip1. We have thus identified Sp1 as an important regulator of the cell cycle in G1 phase.     

Control of the cell cycle

Cell biology has made major progress in identifying the molecules that drive the cell cycle. The evidence accumulating from these studies indicates that derangements in the cell cycle machinery contribute to the uncontrolled cell growth of tumours. The cell cycle machinery has been found to be substantially altered in tumour cells and also may be crucial for carcinogenesis. In this context, various aspects of tumour cell growth have been studied in an effort to understand 1) why tumour cells display uncontrolled growth, 2) why radiation selectively affects growing cells, and 3) whether aspects of the cell cycle and tumour cell growth may be used in tumour diagnosis and prognosis.