http://www.celldiv.com The most accessed research articles published by Cell Division 2012-05-04T00:00:00Z Increasing knowledge on the cell cycle deregulations in cancers has promoted the introduction of phytochemicals, which can either modulate signaling pathways leading to cell cycle regulation or directly alter cell cycle regulatory molecules, in cancer therapy. Most human malignancies are driven by chromosomal translocations or other genetic alterations that directly affect the function of critical cell cycle proteins such as cyclins as well as tumor suppressors, e.g., p53. In this respect, cell cycle regulation and its modulation by curcumin are gaining widespread attention in recent years. Extensive research has addressed the chemotherapeutic potential of curcumin (diferuloylmethane), a relatively non-toxic plant derived polyphenol. The mechanisms implicated are diverse and appear to involve a combination of cell signaling pathways at multiple levels. In the present review we discuss how alterations in the cell cycle control contribute to the malignant transformation and provide an overview of how curcumin targets cell cycle regulatory molecules to assert anti-proliferative and/or apoptotic effects in cancer cells. The purpose of the current article is to present an appraisal of the current level of knowledge regarding the potential of curcumin as an agent for the chemoprevention of cancer via an understanding of its mechanism of action at the level of cell cycle regulation. Taken together, this review seeks to summarize the unique properties of curcumin that may be exploited for successful clinical cancer prevention. http://www.celldiv.com/content/3/1/14 Gaurisankar Sa Tanya Das Cell Division 2008, null:14 2008-10-03T00:00:00Z doi:10.1186/1747-1028-3-14 /content/figures/1747-1028-3-14-toc.gif Cell Division 1747-1028 ${item.volume} 14 2008-10-03T00:00:00Z XML The cyclin-dependent kinases (Cdks) regulate many cellular processes, including the cell cycle, neuronal development, transcription, and posttranscriptional processing. To perform their functions, Cdks bind to specific cyclin subunits to form a functional and active cyclin/Cdk complex. This review is focused on Cyclin K, which was originally considered an alternative subunit of Cdk9, and on its newly identified partners, Cdk12 and Cdk13. We briefly summarize research devoted to each of these proteins. We also discuss the proteins' functions in the regulation of gene expression via the phosphorylation of serine 2 in the C-terminal domain of RNA polymerase II, contributions to the maintenance of genome stability, and roles in the onset of human disease and embryo development. http://www.celldiv.com/content/7/1/12 Jiri Kohoutek Dalibor Blazek Cell Division 2012, null:12 2012-04-18T00:00:00Z doi:10.1186/1747-1028-7-12 /content/figures/1747-1028-7-12-toc.gif Cell Division 1747-1028 ${item.volume} 12 2012-04-18T00:00:00Z XML The cyclin dependent kinase Cdk1 controls the cell cycle, which is best understood in the model organism S. cerevisiae. Research performed during the past decade has significantly improved our understanding of the molecular machinery of the cell cycle. Approximately 75 targets of Cdk1 have been identified that control critical cell cycle events, such as DNA replication and segregation, transcriptional programs and cell morphogenesis. In this review we discuss currently known targets of Cdk1 in the budding yeast S. cerevisiae and highlight the role of Cdk1 in several crucial processes including maintenance of genome stability. http://www.celldiv.com/content/5/1/11 Jorrit Enserink Richard Kolodner Cell Division 2010, null:11 2010-05-13T00:00:00Z doi:10.1186/1747-1028-5-11 /content/figures/1747-1028-5-11-toc.gif Cell Division 1747-1028 ${item.volume} 11 2010-05-13T00:00:00Z XML Inflammation is an important environmental factor that promotes tumourigenesis and the progression of established cancerous lesions, and recent studies have started to dissect the mechanisms linking the two pathologies. These inflammatory and infectious conditions trigger immune and stromal cell release of soluble mediators which facilitate survival and proliferation of tumour cells in a paracrine manner. In addition, (epi-)genetic mutations affecting oncogenes, tumour-suppressor genes, chromosomal rearrangements and amplifications trigger the release of inflammatory mediators within the tumour microenvironment to promote neoplastic growth in an autocrine manner. These two pathways converge in tumour cells and result in activation of the latent signal transducer and activator of transcription 3 (Stat3) which mediates a transcriptional response favouring survival, proliferation and angiogenesis. The abundance of cytokines that activate Stat3 within the tumour microenvironment, which comprises of members of the interleukin (IL) IL6, IL10 and IL17/23 families, underpins a signaling network that simultaneously promotes the growth of neoplastic epithelium, fuels inflammation and suppresses the host's anti-tumour immune response. Accordingly, aberrant and persistent Stat3 activation is a frequent observation in human cancers of epithelial origin and is often associated with poor outcome.Here we summarize insights gained from mice harbouring mutations in components of the Stat3 signaling cascade and in particular of gp130, the shared receptor for the IL6 family of cytokines. We focus on the various feed-back and feed-forward loops in which Stat3 provides the signaling node in cells of the tumour and its microenvironment thereby functionally linking excessive inflammation to neoplastic growth. Although these observations are particularly pertinent to gastrointestinal tumours, we suggest that the tumour's addiction to persistent Stat3 activation is likely to also impact on other epithelial cell-derived cancers. These insights provide clues to the judicious interference of the gp130/Stat3 signaling cascade in therapeutically targeting cancer. http://www.celldiv.com/content/5/1/14 Andrew Jarnicki Tracy Putoczki Matthias Ernst Cell Division 2010, null:14 2010-05-17T00:00:00Z doi:10.1186/1747-1028-5-14 /content/figures/1747-1028-5-14-toc.gif Cell Division 1747-1028 ${item.volume} 14 2010-05-17T00:00:00Z XML Background: In Schizosaccharomyces pombe the SET domain protein, Set3p - together with its interacting partners, Snt1p, and Sif2p - form a complex that aids in preventing cell division failure upon mild cytokinetic stress. Intriguingly, the human orthologs of these genes (MLL5, NCOR2, and TBL1X) are also important for the faithful completion of cytokinesis in tissue culture cells. Since MLL5, NCOR2, and TBL1X form a complex with the histone de-acetylase, HDAC3, we sought to determine if an orthologous counterpart played a regulatory role in fission yeast cytokinesis. Results: In this report we identify the hos2 gene as the fission yeast HDAC3 ortholog. We show that Hos2p physically interacts with Set3p, Snt1p, and Sif2p, and that hos2Delta mutants are indeed compromised in their ability to reliably complete cell division in the presence of mild cytokinetic stresses. Furthermore, we demonstrate that over-expression of hos2 causes severe morphological and cytokinetic defects. Lastly, through recombinase mediated cassette exchange, we show that expression of human HDAC3 complements the cytokinetic defects exhibited by hos2Delta cells. Conclusions: These data support a model in which Hos2p functions as a critical functional component of the Set3p-Snt1p-Sif2p complex with respect to its role in cytokinesis. The ability of human HDAC3 to complement the cytokinesis defects associated with the deletion of the hos2 gene suggests that further analysis of this system could translate into a theoretical framework for understanding how the orthologous MLL5 complex functions to regulate cytokinesis in human cells. http://www.celldiv.com/content/7/1/13 Charnpal Grewal Jack Hickmott Stefan Rentas Jim Karagiannis Cell Division 2012, null:13 2012-05-04T00:00:00Z doi:10.1186/1747-1028-7-13 /content/figures/1747-1028-7-13-toc.gif Cell Division 1747-1028 ${item.volume} 13 2012-05-04T00:00:00Z PDF Senescence and mitotic catastrophe (MC) are two distinct crucial non-apoptotic mechanisms, often triggered in cancer cells and tissues in response to anti-cancer drugs. Chemotherapeuticals and myriad other factors induce cell eradication via these routes. While senescence drives the cells to a state of quiescence, MC drives the cells towards death during the course of mitosis. The senescent phenotype distinguishes tumor cells that survived drug exposure but lost the ability to form colonies from those that recover and proliferate after treatment. Although senescent cells do not proliferate, they are metabolically active and may secrete proteins with potential tumor-promoting activities. The other anti-proliferative response of tumor cells is MC that is a form of cell death that results from abnormal mitosis and leads to the formation of interphase cells with multiple micronuclei. Different classes of cytotoxic agents induce MC, but the pathways of abnormal mitosis differ depending on the nature of the inducer and the status of cell-cycle checkpoints. In this review, we compare the two pathways and mention that they are activated to curb the growth of tumors. Altogether, we have highlighted the possibilities of the use of senescence targeting drugs, mitotic kinases and anti-mitotic agents in fabricating novel strategies in cancer control. http://www.celldiv.com/content/5/1/4 Richa Singh Jasmine George Yogeshwer Shukla Cell Division 2010, null:4 2010-01-21T00:00:00Z doi:10.1186/1747-1028-5-4 /content/figures/1747-1028-5-4-toc.gif Cell Division 1747-1028 ${item.volume} 4 2010-01-21T00:00:00Z XML Monoubiquitination of H2A is a major histone modification in mammalian cells. Understanding how monoubiquitinated H2A (uH2A) regulates DNA-based processes in the context of chromatin is a challenging question. Work in the past years linked uH2A to transcriptional repression by the Polycomb group proteins of developmental regulators. Recently, a number of mammalian deubiquitinating enzymes (DUBs) that catalyze the removal of ubiquitin from H2A have been discovered. These studies provide convincing evidence that H2A deubiquitination is connected with gene activation. In addition, uH2A regulatory enzymes have crucial roles in the cellular response to DNA damage and in cell cycle progression. In this review we will discuss new insights into uH2A biology, with emphasis on the H2A DUBs. http://www.celldiv.com/content/3/1/8 Joseph Vissers Francesco Nicassio Maarten van Lohuizen Pier Paolo Di Fiore Elisabetta Citterio Cell Division 2008, null:8 2008-04-22T00:00:00Z doi:10.1186/1747-1028-3-8 /content/figures/1747-1028-3-8-toc.gif Cell Division 1747-1028 ${item.volume} 8 2008-04-22T00:00:00Z XML The anaphase promoting complex/cyclosome (APC/C) is a multi-subunit E3 ubiquitin ligase playing essential functions in mitosis. It is conserved from yeast to human and relies on two adaptor proteins, Cdc20 and Cdh1, to bring in substrates. Both APCCdc20 and APCCdh1 are implicated in the control of mitosis through mediating ubiquitination and degradation of important mitotic regulators such as cyclin B1, securin, and Plk1. In addition, APCCdh1 is thought to prevent premature S phase entry by limiting the accumulation of mitotic cyclins in G1 and to regulate processes unrelated to cell cycle. In this review, we will summarize our current understanding of APCCdh1 function in cell cycle and beyond. http://www.celldiv.com/content/4/1/2 Min Li Pumin Zhang Cell Division 2009, null:2 2009-01-19T00:00:00Z doi:10.1186/1747-1028-4-2 /content/figures/1747-1028-4-2-toc.gif Cell Division 1747-1028 ${item.volume} 2 2009-01-19T00:00:00Z XML Background: The Positive Transcription Elongation Factor b (P-TEFb) is a complex of Cyclin Dependent Kinase 9 (CDK9) with either cyclins T1, T2 or K. The complex phosphorylates the C-Terminal Domain of RNA polymerase II (RNAPII) and negative elongation factors, stimulating productive elongation by RNAPII, which is paused after initiation. P-TEFb is recruited downstream of the promoters of many genes, including primary response genes, upon certain stimuli. Flavopiridol (FVP) is a potent pharmacological inhibitor of CDK9 and has been used extensively in cells as a means to inhibit CDK9 activity. Inhibition of P-TEFb complexes has potential therapeutic applications. Results: It has been shown that Lipopolysaccharide (LPS) stimulates the recruitment of P-TEFb to Primary Response Genes (PRGs) and proposed that P-TEFb activity is required for their expression, as the CDK9 inhibitor DRB prevents localization of RNAPII in the body of these genes. We have previously determined the effects of FVP in global gene expression in a variety of cells and surprisingly observed that FVP results in potent upregulation of a number of PRGs in treatments lasting 4-24 h. Because inhibition of CDK9 activity is being evaluated in pre-clinical and clinical studies for the treatment of several pathologies, it is important to fully understand the short and long term effects of its inhibition. To this end, we determined the immediate and long-term effect of FVP in the expression of several PRGs. In exponentially growing normal human fibroblasts, the expression of several PRGs including FOS, JUNB, EGR1 and GADD45B, was rapidly and potently downregulated before they were upregulated following FVP treatment. In serum starved cells re-stimulated with serum, FVP also inhibited the expression of these genes, but subsequently, JUNB, GADD45B and EGR1 were upregulated in the presence of FVP. Chromatin Immunoprecipitation of RNAPII revealed that EGR1 and GADD45B are transcribed at the FVP-treatment time points where their corresponding mRNAs accumulate. These results suggest a possible stress response triggered by CDK9 inhibition than ensues transcription of certain PRGs. Conclusions: We have shown that certain PRGs are transcribed in the presence of FVP in a manner that might be independent of CDK9, suggesting a possible alternative mechanism for their transcription when P-TEFb kinase activity is pharmacologically inhibited. These results also show that the sensitivity to FVP is quite variable, even among PRGs. http://www.celldiv.com/content/7/1/11 Havva Keskin Judit Garriga Daphne Georlette Xavier Grana Cell Division 2012, null:11 2012-03-29T00:00:00Z doi:10.1186/1747-1028-7-11 /content/figures/1747-1028-7-11-toc.gif Cell Division 1747-1028 ${item.volume} 11 2012-03-29T00:00:00Z XML The NIMA-related kinases represent a family of serine/threonine kinases implicated in cell cycle control. The founding member of this family, the NIMA kinase of Aspergillus nidulans, as well as the fission yeast homologue Fin1, contribute to multiple aspects of mitotic progression including the timing of mitotic entry, chromatin condensation, spindle organization and cytokinesis. Mammals contain a large family of eleven NIMA-related kinases, named Nek1 to Nek11. Of these, there is now substantial evidence that Nek2, Nek6, Nek7 and Nek9 also regulate mitotic events. At least three of these kinases, as well as NIMA and Fin1, have been localized to the microtubule organizing centre of their respective species, namely the centrosome or spindle pole body. Here, they have important functions in microtubule organization and mitotic spindle assembly. Other Nek kinases have been proposed to play microtubule-dependent roles in non-dividing cells, most notably in regulating the axonemal microtubules of cilia and flagella. In this review, we discuss the evidence that NIMA-related kinases make a significant contribution to the orchestration of mitotic progression and thereby protect cells from chromosome instability. Furthermore, we highlight their potential as novel chemotherapeutic targets. http://www.celldiv.com/content/2/1/25 Laura O'Regan Joelle Blot Andrew Fry Cell Division 2007, null:25 2007-08-29T00:00:00Z doi:10.1186/1747-1028-2-25 /content/figures/1747-1028-2-25-toc.gif Cell Division 1747-1028 ${item.volume} 25 2007-08-29T00:00:00Z XML