The major mission of the cell division cycle is a faithful and complete duplication of the genome followed by an equal partitioning of chromosomes to subsequent cell generations. In this review, we discuss the advances in our understanding of how mammalian cells control the fidelity of these fundamental processes when exposed to diverse genotoxic insults. We focus on the most recent insights into the molecular pathways that link the sites of DNA lesions with the cell cycle machinery in specific phases of the cell cycle. We also highlight the potential of a new technology allowing direct visualization of molecular interactions and redistribution of checkpoint proteins in live cell nuclei, and document the emerging significance of live-cell imaging for elucidation of the spatio-temporal organization of the DNA damage response network.
- MeSH
- Models, Biological MeSH
- Cell Nucleus metabolism MeSH
- Cell Cycle * MeSH
- Time Factors MeSH
- Checkpoint Kinase 2 MeSH
- DNA genetics MeSH
- G1 Phase MeSH
- G2 Phase MeSH
- Genome MeSH
- Nuclear Proteins physiology MeSH
- Humans MeSH
- Models, Genetic MeSH
- DNA Repair * MeSH
- DNA Damage * MeSH
- Protein Serine-Threonine Kinases metabolism MeSH
- Cell Cycle Proteins physiology MeSH
- S Phase MeSH
- Signal Transduction * MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
All life on earth must cope with constant exposure to DNA-damaging agents such as the Sun's radiation. Highly conserved DNA-repair and cell-cycle checkpoint pathways allow cells to deal with both endogenous and exogenous sources of DNA damage. How much an individual is exposed to these agents and how their cells respond to DNA damage are critical determinants of whether that individual will develop cancer. These cellular responses are also important for determining toxicities and responses to current cancer therapies, most of which target the DNA.
... [et al.] -- The beginning of the microRNA era for cell cycle control / Kenichi Yoshida -- Cycles, systems ... ... Janecka -- TGF[beta] : a unique and powerful negative regulator of the cell cycle in human myeloid leukemia ... ... and cell cycle regulation / Ota Fuchs -- Transcription factor C/EBP[alpha] and its effect on cell cycle ... ... -- The role of cell cycle control genes in the pathogenesis of human hematological neoplasms / Luâis ... ... Vieira and Maria Gomes da Silva -- Cell cycle control in drosophila / Zohra Rahmani -- Cell cycle control ...
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- MeSH
- Cell Cycle physiology MeSH
- Cell Cycle Proteins physiology MeSH
- Publication type
- Monograph MeSH
- Conspectus
- Buněčná biologie. Cytologie
- NML Fields
- biochemie
- biologie
Cell cycle represents not only a tightly orchestrated mechanism of cell replication and cell division but it also plays an important role in regulation of cell fate decision. Particularly in the context of pluripotent stem cells or multipotent progenitor cells, regulation of cell fate decision is of paramount importance. It has been shown that human embryonic stem cells (hESCs) show unique cell cycle characteristics, such as short doubling time due to abbreviated G1 phase; these properties change with the onset of differentiation. This review summarizes the current understanding of cell cycle regulation in hESCs. We discuss cell cycle properties as well as regulatory machinery governing cell cycle progression of undifferentiated hESCs. Additionally, we provide evidence that long-term culture of hESCs is accompanied by changes in cell cycle properties as well as configuration of several cell cycle regulatory molecules.
- MeSH
- Cell Differentiation MeSH
- Cell Culture Techniques MeSH
- Cell Cycle physiology MeSH
- Embryonic Stem Cells cytology physiology MeSH
- Cell Cycle Checkpoints physiology MeSH
- Humans MeSH
- Pluripotent Stem Cells cytology physiology MeSH
- Cell Cycle Proteins metabolism physiology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
In response to diverse genotoxic stresses, cells activate DNA damage checkpoint pathways to protect genomic integrity and promote survival of the organism. Depending on DNA lesions and context, damaged cells with alarmed checkpoints can be eliminated by apoptosis or silenced by cellular senescence, or can survive and resume cell cycle progression upon checkpoint termination. Over the past two years a plethora of mechanistic studies have provided exciting insights into the biology and pathology of checkpoint initiation and signal propagation, and have revealed the various ways in which the response can be terminated: through recovery, adaptation or cancer-prone subversion. Such studies highlight the dynamic nature of these processes and help us to better understand the molecular basis, spatiotemporal orchestration and biological significance of the DNA damage response in normal and cancerous cells.
DNA lesions trigger the DNA damage response (DDR) machinery, which protects genomic integrity and sustains cellular survival. Increasing data underline the significance of the integrity of the DDR pathway in chemotherapy response. According to a recent work, persistent exposure of A549 lung carcinoma cells to doxorubicin induces an initial DDR-dependent checkpoint response, followed by a later DDR-independent, but p27(Kip1)-dependent one. Prompted by the above report and to better understand the involvement of the DDR signaling after chemotherapeutic stress, we examined the potential role of the canonical DDR pathway in A549 cells treated with doxorubicin. Exposure of A549 cells, prior to doxorubicin treatment, to ATM, ATR and DNA-PKcs inhibitors either alone or in various combinations, revealed that the earlier documented two-step response was DDR-dependent in both steps. Notably, inhibition of both ATM and ATR or selective inhibition of ATM or DNA-PKcs resulted in cell-cycle re-entry despite the increased levels of p27(Kip1) at all time points analyzed. We further investigated the regulation of p27(Kip1) protein levels in the particular setting. Our results showed that the protein status of p27(Kip1) is mainly determined by p38-MAPK, whereas the role of SKP2 is less significant in the doxoroubicin-treated A549 cells. Cumulatively, we provide evidence that the DNA damage signaling is responsible for the prolonged cell cycle arrest observed after persistent chemotherapy-induced genotoxic stress. In conclusion, precise identification of the molecular mechanisms that are activated during the chemotherapeutic cycles could potentially increase the sensitization to the therapy applied.
- MeSH
- Ataxia Telangiectasia Mutated Proteins antagonists & inhibitors MeSH
- A549 Cells MeSH
- Chromones pharmacology MeSH
- Doxorubicin pharmacology MeSH
- Cyclin-Dependent Kinase Inhibitor p27 physiology MeSH
- Caffeine pharmacology MeSH
- G2 Phase Cell Cycle Checkpoints drug effects MeSH
- Humans MeSH
- p38 Mitogen-Activated Protein Kinases metabolism MeSH
- Morpholines pharmacology MeSH
- DNA Damage MeSH
- DNA-Activated Protein Kinase antagonists & inhibitors MeSH
- S-Phase Kinase-Associated Proteins metabolism MeSH
- Antineoplastic Agents pharmacology MeSH
- Pyrones pharmacology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Epidemiological data indicate that selenium status is inversely connected with cancer risk. Animal and human studies have demonstrated that most inorganic and organic forms of selenium compounds have an anticancer action. This work investigated the impact of organic selenium on the multiple signalling pathways involved in the inhibition of the viability of prostate cancer cells. Prostate adenocarcinoma cells (PC-3) were incubated with seleno-l-methionine (SeMet) at four concentrations and cell viability and programmed cell death were determined by the WST-1, BrdU assays and Tali image based cytometer. The expression of chosen cell-cycle regulatory genes was determined by real-time RT-PCR analysis and confirmed at the protein level. SeMet treatment of PC-3 cells resulted in an inhibition of cell proliferation in a dose- and time-dependent manner. The inhibition of proliferation correlated with the up-regulation of gene expression and the protein levels of CCNG1, CHEK1, CDKN1C and GADD45A, whereas SeMet down-regulated the expression of CCNA1 and CDK6 genes. Therefore SeMet inhibits the proliferative activity of prostate cancer cells by a direct influence on the expression of genes involved in the regulation of cell cycle progression.
- MeSH
- Adenocarcinoma drug therapy genetics MeSH
- Apoptosis genetics drug effects MeSH
- Time Factors MeSH
- Genes, cdc drug effects MeSH
- Gene Expression drug effects MeSH
- Cell Line, Tumor * drug effects MeSH
- Prostatic Neoplasms * drug therapy genetics MeSH
- Reverse Transcriptase Polymerase Chain Reaction MeSH
- Cell Proliferation drug effects MeSH
- Cell Cycle Proteins genetics drug effects MeSH
- Gene Expression Regulation, Neoplastic MeSH
- Selenium MeSH
- Selenomethionine * administration & dosage MeSH
- Statistics as Topic MeSH
- In Vitro Techniques MeSH
- Cell Survival * drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Blotting, Western MeSH
- Publication type
- Evaluation Study MeSH
- Research Support, Non-U.S. Gov't MeSH
The past several years have witnessed a dramatic accumulation of experimental and clinical evidence supporting the notion that the cell cycle machinery is commonly targeted on oncogenesis. While numerous cell cycle regulators qualify as proto-oncogenes or tumour suppressors and their aberrations may provide direct proliferative advantage to cancer cells, defects in checkpoint mechanisms act more indirectly yet affect both tumour progression and response to anticancer therapy. In this review, the ways that cell cycle defects contribute to oncogenesis are briefly illustrated and the emerging benefits of the newly gained insights into the cell cycle clock for clinical oncology are critically considered. Given the many reviews on the subject, emphasis is put on concepts rather than comprehensive treatment of the selected topics, with particular attention given to controversial issues, unorthodox phenomena, and the challenge facing the 'cell cycle and cancer field' at the transition to the next millennium.
- MeSH
- Cell Cycle genetics physiology MeSH
- Humans MeSH
- Cell Transformation, Neoplastic genetics pathology MeSH
- Oncogenes MeSH
- Genes, Suppressor MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
The objective of this study was to describe co-expression correlations of cell cycle regulatory genes in multiple myeloma (MM) and plasma cell leukemia (PCL). Our results highlight the presence of dynamic equilibrium between co-expression of activator and inhibitor gene sets. Moreover inhibitor set is more sensitive to the activator changes, not vice versa. We have shown that CDKN2A expression is associated with short-term survival in newly diagnosed MM patients (survival was 30.3 ± 3.9 months for 'low' expressed and 7.5 ± 5.6 months for 'high' expressed group, p<0.0001). Moreover low-expression CDKN2A group showed time-to-progression benefit in newly diagnosed patients (remission was 20.8 ± 3.6 months for 'low' and 8.4 ± 2.7 months for 'high' expressed group, p<0.0001) as well as in whole studied cohort of MM patients (remission was 20.8 ± 2.8 months for 'low' and 9.8 ± 1.1 months for 'high' expressed group, p<0.0001). The overexpression of inhibitors can be explained as a compensatory reaction to growing "oncogenic stress".
- MeSH
- Survival Analysis MeSH
- Cell Cycle genetics MeSH
- Time Factors MeSH
- Genes, cdc * MeSH
- HeLa Cells MeSH
- Cyclin-Dependent Kinase Inhibitor p16 genetics metabolism MeSH
- Middle Aged MeSH
- Humans MeSH
- Multiple Myeloma diagnosis genetics MeSH
- Tumor Cells, Cultured MeSH
- Leukemia, Plasma Cell diagnosis genetics MeSH
- Prognosis MeSH
- Disease Progression MeSH
- Gene Expression Regulation, Neoplastic MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
