共查询到20条相似文献,搜索用时 15 毫秒
1.
《Developmental cell》2022,57(5):638-653.e5
- Download : Download high-res image (157KB)
- Download : Download full-size image
2.
Elham Farshadi Jie Yan Pierre Leclere Albert Goldbeter 《Cell cycle (Georgetown, Tex.)》2019,18(1):16-33
We previously identified a tight bidirectional phase coupling between the circadian clock and the cell cycle. To understand the role of the CLOCK/BMAL1 complex, representing the main positive regulator of the circadian oscillator, we knocked down Bmal1 or Clock in NIH3T33C mouse fibroblasts (carrying fluorescent reporters for clock and cell cycle phase) and analyzed timing of cell division in individual cells and cell populations. Inactivation of Bmal1 resulted in a loss of circadian rhythmicity and a lengthening of the cell cycle, originating from delayed G2/M transition. Subsequent molecular analysis revealed reduced levels of Cyclin B1, an important G2/M regulator, upon suppression of Bmal1 gene expression. In complete agreement with these experimental observations, simulation of Bmal1 knockdown in a computational model for coupled mammalian circadian clock and cell cycle oscillators (now incorporating Cyclin B1 induction by BMAL1) revealed a lengthening of the cell cycle. Similar data were obtained upon knockdown of Clock gene expression. In conclusion, the CLOCK/BMAL1 complex controls cell cycle progression at the level of G2/M transition through regulation of Cyclin B1 expression. 相似文献
3.
4.
In response to DNA damage, a cell can be forced to permanently exit the cell cycle and become senescent. Senescence provides an early barrier against tumor development by preventing proliferation of cells with damaged DNA. By studying single cells, we show that Cdk activity persists after DNA damage until terminal cell cycle exit. This low level of Cdk activity not only allows cell cycle progression, but also promotes cell cycle exit at a decision point in G2 phase. We find that residual Cdk1/2 activity is required for efficient p21 production, allowing for nuclear sequestration of Cyclin B1, subsequent APC/CCdh1‐dependent degradation of mitotic inducers and induction of senescence. We suggest that the same activity that triggers mitosis in an unperturbed cell cycle enforces senescence in the presence of DNA damage, ensuring a robust response when most needed. 相似文献
5.
Diana Walluscheck Kathrin Reissig Khuloud Bajbouj Oliver Ullrich Roland Hartig Hala Gali‐Muhtasib Antje Diestel Albert Roessner Regine Schneider‐Stock 《Journal of cellular and molecular medicine》2011,15(7):1528-1541
Besides the well‐understood DNA damage response via establishment of G2 checkpoint arrest, novel studies focus on the recovery from arrest by checkpoint override to monitor cell cycle re‐entry. The aim of this study was to investigate the role of Chk1 in the recovery from G2 checkpoint arrest in HCT116 (human colorectal cancer) wt, p53–/– and p21–/– cell lines following H2O2 treatment. Firstly, DNA damage caused G2 checkpoint activation via Chk1. Secondly, overriding G2 checkpoint led to (i) mitotic slippage, cell cycle re‐entry in G1 and subsequent G1 arrest associated with senescence or (ii) premature mitotic entry in the absence of p53/p21WAF1 causing mitotic catastrophe. We revealed subtle differences in the initial Chk1‐involved G2 arrest with respect to p53/p21WAF1: absence of either protein led to late G2 arrest instead of the classic G2 arrest during checkpoint initiation, and this impacted the release back into the cell cycle. Thus, G2 arrest correlated with downstream senescence, but late G2 arrest led to mitotic catastrophe, although both cell cycle re‐entries were linked to upstream Chk1 signalling. Chk1 knockdown deciphered that Chk1 defines long‐term DNA damage responses causing cell cycle re‐entry. We propose that recovery from oxidative DNA damage‐induced G2 arrest requires Chk1. It works as cutting edge and navigates cells to senescence or mitotic catastrophe. The decision, however, seems to depend on p53/p21WAF1. The general relevance of Chk1 as an important determinant of recovery from G2 checkpoint arrest was verified in HT29 colorectal cancer cells. 相似文献
6.
Genistein is an isoflavonic phyto-oestrogen contained in soya beans. It is thought to display anti-cancer effects. This study was designed to investigate its effect on human intestinal colon cancer Caco-2 cells. MTT assay, flow cytometric analysis and western blotting were used to investigate the effect of genistein on cell proliferation, cell cycle progression and protein alterations of selected cell cycle-related proteins in Caco-2 cells. Our results showed that genistein and daidzein significantly suppressed cell proliferation. Genistein treatment was demonstrated to modulate cell cycle distribution through accumulation of cells at G2/M phase, with a significant decreasing effect of Cyclin B1 and Serine/threonine-protein kinase 2 (Chk2) proteins expression. However, daidzein did not alter the cell cycle progression in Caco-2 cells. All these observation strongly indicate that genistein has anti-proliferative effect in human intestinal colon cancer Caco-2 cells through the down-regulation of cell cycle check point proteins, Cyclin B1 and Chk2. 相似文献
7.
8.
In order to maintain a stable genome, cells need to detect and repair DNA damage before they complete the division cycle. To this end, cell cycle checkpoints prevent entry into the next cell cycle phase until the damage is fully repaired. Proper reentry into the cell cycle, known as checkpoint recovery, requires that a cell retains its original cell cycle state during the arrest. Here, we have identified Tousled‐like kinase 2 (Tlk2) as an important regulator of recovery after DNA damage in G2. We show that Tlk2 regulates the Asf1A histone chaperone in response to DNA damage and that depletion of Asf1A also produces a recovery defect. Both Tlk2 and Asf1A are required to restore histone H3 incorporation into damaged chromatin. Failure to do so affects expression of pro‐mitotic genes and compromises the cellular competence to recover from damage‐induced cell cycle arrests. Our results demonstrate that Tlk2 promotes Asf1A function during the DNA damage response in G2 to allow for proper restoration of chromatin structure at the break site and subsequent recovery from the arrest. 相似文献
9.
Progression through the G1-phase of the on-going cell cycle 总被引:7,自引:0,他引:7
Boonstra J 《Journal of cellular biochemistry》2003,90(2):244-252
Cell cycle progression is dependent upon the action of cyclins and their partners the cyclin dependent kinases (CDKs). Each cell cycle phase has its own characteristic cyclin-CDK combination, cyclin D-CDK4,6 and cyclin E-CDK2 being responsible for progression through G(1)-phase into S-phase. Progression through G(1)-phase is regulated by signal transduction cascades activated by polypeptide growth factors and by extracellular matrix (ECM) components. Studies aiming to unravel the molecular mechanism by which these extracellular components activate the cyclin-CDK complexes in the G(1)-phase, are usually performed using serum-starved cells (G(0) cells). These cells are activated by addition of growth factors, or the cells are detached from the substratum by trypsinization and subsequently allowed to re-attach. An alternative approach, however, is to study the effects of growth factors and attachment in the ongoing cell cycle by synchronization of the cells by the mitotic shake-off method. These cells are not serum starved and not actively detached from the substratum. In this contribution it is shown that both methods yield significant different results. These observations demonstrate that data obtained with model systems should be interpreted with care, especially if the findings are used to explain cell cycle progression in cells in an intact organism. 相似文献
10.
Miaomiao Jin Jingyu Li Ruikun Hu Baijie Xu Guanliang Huang Weilai Huang Bo Chen Jie He Ying Cao 《遗传学报》2021,48(1):63-74
Cyclin-dependent kinase 1 (CDK1) plays an essential role in cell cycle regulation.However,as mouse Cdk1embryos die early,the role of CDK1 in regulating the cell cycle and embryo development remains unclear.Here,we showed that zebrafish cdk1~(-/-)embryos exhibit severe microphthalmia accompanied by multiple defects in S phase entry,M phase progression,and cell differentiation but not in interkinetic nuclear migration.We identified Top2a as a potential downstream target and cyclin A2 and cyclin B1 as partners of Cdk1 in cell cycle regulation via an in silico analysis.While depletion of either cyclin A2 or Top2a led to the decreased S phase entry in zebrafish retinal cells,the depletion of cyclin B1 led to M phase arrest.Moreover,phosphorylation of Top2a at serine 1213 (S1213) was nearly abolished in both cdk1 and ccna2mutants,but not in ccnb1 mutants.Furthermore,overexpression of TOP2A~(S1213D),the phosphomimetic form of human TOP2A,rescued S phase entry and alleviated the microphthalmia defects in both cdk1~(-/-)and ccna2~(-/-)embryos.Taken together,our data suggest that Cdk1 interacts with cyclin A2 to regulate S phase entry partially through Top2a phosphorylation and interacts with cyclin B1 to regulate M phase progression. 相似文献
11.
Shan Xu Peng Guo Yang Gao Qi Shi Dalin He Yang Gao Hailong Zhang 《Biochemical and biophysical research communications》2013
Acyldepsipeptides are a group of potent antibiotics discovered in the secondary metabolites of Streptomyces species. However, besides the function of antibiotics, no other activities have been reported about these important compounds so far. In the course of searching the natural products as chemotherapeutic agents for renal cell carcinoma, we found that ADEP1, a major metabolic component of Streptomyces hawaiiensis NRRL 15010, could effectively inhibit the growth of 786-O, 769-P, and ACHN renal carcinoma cells in MTT assay. Flow cytometric analysis demonstrated that ADEP1 could block the cell cycle arrested at G1 phase. Moreover, it was found that ADEP1 down-regulated the expressions of cyclin D1, CDK4 and PCNA and inhibited activity of MAPK–ERK pathway by detection of decreased expression of phosphorylated ERK1/2 and c-Fos in 786-O and 769-P cells by Western blotting. To our knowledge, this is the first report concerning to the antitumor activities of acyldepsipeptides. Based on these results, ADEP1 may become a promising lead compound to be developed a novel chemotherapeutic agent for treatment of renal carcinoma. 相似文献
12.
Progression of cells from G2 phase of the cell cycle to mitosis is a tightly regulated cellular process that requires activation of the Cdc2 kinase, which determines onset of mitosis in all eukaryotic cells. In both human and fission yeast(Schizosaccharomyces pombe) cells, the activity of Cdc2 is regulated in part by the phosphorylation status of tyrosine 15 (Tyrl5) on Cdc2, which is phosphorylated by Weel kinase during late G2 and is rapidly dephosphorylated by the Cdc25 tyrosine phosphatase to trigger entry into mitosis. These Cdc2 regulators are the downstream targets of two wellcharacterized G2/M checkpoint pathways which prevent cells from entering mitosis when cellular DNA is damaged or when DNA replication is inhibited. Increasing evidence suggests that Cdc2 is also commonly targeted by viral proteins,which modulate host cell cycle machinery to benefit viral survival or replication. In this review, we describe the effect of viral protein R (Vpr) encoded by human immunodeficiency virus type 1 (HIV-Ⅰ) on cell cycle G2/M regulation. Based on our current knowledge about this viral effect, we hypothesize that Vpr induces cell cycle G2 arrest through a mechanism that is to some extent different from the classic G2/M checkpoints. One the unique features distinguishing Vpr-induced G2 arrest from the classic checkpoints is the role of phosphatase 2A (PP2A) in Vpr-induced G2 arrest.Interestingly, PP2A is targeted by a number of other viral proteins including SV40 small T antigen, polyomavirus T antigen, HTLV Tax and adenovirus E4orf4. Thus an in-depth understanding of the molecular mechanisms underlying Vpr-induced G2 arrest will provide additional insights into the basic biology of cell cycle G2/M regulation and into the biological significance of this effect during host-pathogen interactions. 相似文献
13.
14.
George Skalka Holly Hall Joanna Somers Martin Bushell Anne Willis 《Cell cycle (Georgetown, Tex.)》2019,18(9):963-975
Common hallmarks of cancer include the dysregulation of cell cycle progression and the acquisition of genome instability. In tumors, G1 cell cycle checkpoint induction is often lost. This increases the reliance on a functional G2/M checkpoint to prevent progression through mitosis with damaged DNA, avoiding the introduction of potentially aberrant genetic alterations. Treatment of tumors with ionizing radiation (IR) utilizes this dependence on the G2/M checkpoint. Therefore, identification of factors which regulate this process could yield important biomarkers for refining this widely used cancer therapy. Leucine zipper and ICAT domain containing (LZIC) downregulation has been associated with the development of IR-induced tumors. However, despite LZIC being highly conserved, it has no known molecular function. We demonstrate that LZIC knockout (KO) cell lines show a dysregulated G2/M cell cycle checkpoint following IR treatment. In addition, we show that LZIC deficient cells competently activate the G1 and early G2/M checkpoint but fail to maintain the late G2/M checkpoint after IR exposure. Specifically, this defect was found to occur downstream of PIKK signaling. The LZIC KO cells demonstrated severe aneuploidy indicative of genomic instability. In addition, analysis of data from cancer patient databases uncovered a strong correlation between LZIC expression and poor prognosis in several cancers. Our findings suggest that LZIC is functionally involved in cellular response to IR, and its expression level could serve as a biomarker for patient stratification in clinical cancer practice. 相似文献
15.
The role of NBS1 in DNA double strand break repair, telomere stability, and cell cycle checkpoint control 总被引:10,自引:0,他引:10
The genomes of eukaryotic cells are under continuous assault by environmental agents and endogenous metabolic byproducts. Damage induced in DNA usually leads to a cascade of cellular events, the DNA damage response. Failure of the DNA damage response can lead to development of malignancy by reducing the efficiency and fidelity of DNA repair. The NBS1 protein is a component of the MRE11/RAD50/NBS 1 complex (MRN) that plays a critical role in the cellular response to DNA damage and the maintenance of chromosomal integrity. Mutations in the NBS1 gene are responsible for Nijmegen breakage syndrome (NBS), a hereditary disorder that imparts an increased predisposition to development of malignancy. The phenotypic characteristics of cells isolated from NBS patients point to a deficiency in the repair of DNA double strand breaks. Here, we review the current knowledge of the role of NBS1 in the DNA damage response. Emphasis is placed on the role of NBS1 in the DNA double strand repair, modulation of the DNA damage sensing and signaling, cell cycle checkpoint control and maintenance oftelomere stability. 相似文献
16.
《Cell cycle (Georgetown, Tex.)》2013,12(6):1217-1234
HIV-1 Tat triggers intrinsic and extrinsic apoptosis pathways in both infected and uninfected cells and plays an important role in the pathogenesis of AIDS. Knocking down Tip60, an interactive protein of Tat, leads to the impairment of cell cycle progression, indicating a key role of Tip60 in cell cycle control. We found that Tip60 interacts with Plk1 through its ZnFMYST domain, and that this interaction is enhanced in the G2/M phase. In addition, cyclin B1 was confirmed to interact with the ZnF domain of Tip60. Immunofluorescence imaging showed that Tip60 co-localizes with both Plk1 and cyclin B1 at the centrosome during the mitotic phase and to the mid-body during cytokinesis. Further experiments revealed that Tip60 forms a ternary complex with Plk1 and cyclin B1 and acetylates Plk1 but not cyclin B1. HIV-1 Tat likely forms a quaternary complex with Tip60, cyclin B1 and Plk1. Fluorescent microscopy showed that Tat causes an unscheduled nuclear translocation of both cyclin B1 and Plk1, causing their co-localization with Tip60 in the nucleus. Tat, Tip60, cyclin B1 and Plk1 interactions provide new a mechanistic explanation for Tat-mediated cell cycle dysregulation and apoptosis. 相似文献
17.
Angela Poehlmann Kathrin Reissig Peter Schönfeld Diana Walluscheck Antje Schinlauer Roland Hartig Wiebke Lessel Thomas Guenther Andrew Silver Albert Roessner 《Journal of cellular and molecular medicine》2013,17(12):1619-1631
The production of hydrogen peroxide (H2O2) drives tumourigenesis in ulcerative colitis (UC). Recently, we showed that H2O2 activates DNA damage checkpoints in human colonic epithelial cells (HCEC) through c‐Jun N‐terminal Kinases (JNK) that induces p21WAF1. Moreover, caspases circumvented the G1/S and intra‐S checkpoints, and cells accumulated in G2/M. The latter observation raised the question of whether repeated H2O2 exposures alter JNK activation, thereby promoting a direct passage of cells from G2/M arrest to driven cell cycle progression. Here, we report that increased proliferation of repeatedly H2O2‐exposed HCEC cells (C‐cell cultures) was associated with (i) increased phospho‐p46 JNK, (ii) decreased total JNK and phospho‐p54 JNK and (iii) p21WAF1 down‐regulation. Altered JNK activation and p21WAF1 down‐regulation were accompanied by defects in maintaining G2/M and mitotic spindle checkpoints through adaptation, as well as by apoptosis resistance following H2O2 exposure. This may cause increased proliferation of C‐cell cultures, a defining initiating feature in the inflammation‐carcinoma pathway in UC. We further suggest that dysregulated JNK activation is attributed to a non‐apoptotic function of caspases, causing checkpoint adaptation in C‐cell cultures. Additionally, loss of cell‐contact inhibition and the overcoming of senescence, hallmarks of cancer, contributed to increased proliferation. Furthermore, there was evidence that p54 JNK inactivation is responsible for loss of cell‐contact inhibition. We present a cellular model of UC and suggest a sinusoidal pattern of proliferation, which is triggered by H2O2‐induced reactive oxygen species generation, involving an interplay between JNK activation/inactivation, p21WAF1, c‐Fos, c‐Jun/phospho‐c‐Jun, ATF2/phospho‐ATF2, β‐catenin/TCF4‐signalling, c‐Myc, CDK6 and Cyclin D2, leading to driven cell cycle progression. 相似文献
18.
Zbigniew Darzynkiewicz 《Journal of cellular biochemistry》1995,58(2):151-159
There is a strong evidence that administration of antitumor drugs triggers apoptotic death of target cells. A characteristic feature of appotosis is active participation of the affected cell in its demise. Attempts have been made, therefore, to potentiate the cytotoxicity of a variety of agents by modulating the propensity of cells to respond by apoptosis. Several strategies to enhance apoptosis that involve modulation of the cell cycle or differentiation are discussed. Loss of control of the G1 checkpoint in tumor cells allows one to design treatments that arrest normal cells at the checkpoint and attempt to selectively kill tumor cells with S phase specific drugs. The possibility of a restoration of the apoptosis triggering function of the tumor suppressor gene p53 when the G1 checkpoint function is abolished is expected to increase tumor cells' sensitivity to S phase poisons. Because induction of apoptosis by many antitumor drugs is cell cycle phase specific, drug combinations that preferentially trigger apoptosis at different phases of the cycle, or recruitment of cells to the sensitive phase, offer another antitumor strategy. There is also evidence that apoptosis is potentiated when cell differentiation is triggered follwing DNA damage. This observation suggests that strategies which combine DNA damaging and differentiating drugs, under conditions where the latter are administered following DNA damage caused by the former, may be successful. 相似文献
19.
Choresca CH Koo OJ Oh HJ Hong SG Gomez DK Kim JH Lee BC Park SC 《Cell biology international》2009,33(1):65-70
One of the most important factors determining the success of the development of cloned embryos is the cell cycle stage of the donor cells. We investigated the effects of serum starvation, culturing to confluence and roscovitine treatment on the cell cycle synchronization of goldfish caudal fin-derived fibroblasts by flow cytometric analysis. The results show that culturing the cells to confluence (85.5%) and roscovitine treatment (82.71%) yield a significantly higher percentage of cells arrested in the G0/G1 (P < 0.05) phase than serum starvation (62.85%). Different concentrations of roscovitine (5, 10, or 15 μM) induce cell cycle arrest at the G0/G1 phase. 相似文献
20.
Min-Hua Rong Jian-Di Li Lu-Yang Zhong Yu-Zhen Huang Juan Chen Li-Yuan Xie Rong-Xing Qin Xiao-Lian He Zhan-Hui Zhu Su-Ning Huang Xian-Guo Zhou 《Experimental biology and medicine (Maywood, N.J.)》2022,247(5):395
In our studies, cyclin B1 (CCNB1) mRNA and protein were overexpressed in hepatocellular carcinoma (HCC) tissues compared with non-HCC tissues. Moreover, CCNB1 was overexpressed in the serum of HCC patients. The expression of CCNB1 was associated with several crucial clinicopathologic characteristics, and the HCC patients with overexpressed CCNB1 had worse overall survival outcomes. In the screening of interactional genes, a total of 266 upregulated co-expression genes, which were positively associated with CCNB1, were selected from the datasets, and 67 downregulated co-expression genes, which were negatively associated with CCNB1, were identified. The key genes might be functionally enriched in DNA replication and the cell cycle pathways. CDC20, CCNA2, PLK1, and FTCD were selected for further research because they were highly connected in the protein-protein interaction networks. Upregulated CDC20, CCNA2, and PLK1 and downregulated FTCD might result in undesirable overall survival outcomes for HCC patients. The univariate Cox analysis results showed that CDC20 and PLK1 might be two independent risk factors, while FTCD might be protective in HCC. Therefore, CCNB1 may participate in the cell cycle of HCC by regulating DNA replication, and CCNB1 may provide a direction for the diagnosis of early-stage HCC and targeted HCC therapy. 相似文献