Malumbres M, Barbacid MCell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9: 153-166

Cell Division and Cancer Group, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain.
Nature Reviews Cancer (Impact Factor: 37.4). 04/2009; 9(3):153-66. DOI: 10.1038/nrc2602
Source: PubMed


Tumour-associated cell cycle defects are often mediated by alterations in cyclin-dependent kinase (CDK) activity. Misregulated CDKs induce unscheduled proliferation as well as genomic and chromosomal instability. According to current models, mammalian CDKs are essential for driving each cell cycle phase, so therapeutic strategies that block CDK activity are unlikely to selectively target tumour cells. However, recent genetic evidence has revealed that, whereas CDK1 is required for the cell cycle, interphase CDKs are only essential for proliferation of specialized cells. Emerging evidence suggests that tumour cells may also require specific interphase CDKs for proliferation. Thus, selective CDK inhibition may provide therapeutic benefit against certain human neoplasias.

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Available from: Marcos Malumbres, Oct 02, 2015
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    • "These checkpoints, which occur at the G 1 /S phase transition, the G 2 /M phase transition, and during mitosis before cell division, are tightly regulated by nuclear serine-threonine kinases, including cyclin-dependent kinases (Cdks), Polo-like kinases (Plks), and Aurora kinases [2]. In cancer, these kinases are often dysregulated, promoting uncontrolled cell proliferation and aberrant cell division [1]. Dysregulated expression of different Plk family members has been documented in many cancer types and has been associated with poor prognosis, leading to an enhanced interest in these kinases as promising targets for anticancer drug development [3]. "
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    ABSTRACT: Polo-like kinases (Plks) are a family of serine-threonine kinases that regulate multiple intracellular processes including DNA replication, mitosis, and stress response. Plk1, the most well understood family member, regulates numerous stages of mitosis and is overexpressed in many cancers. Plk inhibitors are currently under clinical investigation, including phase III trials of volasertib, a Plk inhibitor, in acute myeloid leukemia and rigosertib, a dual inhibitor of Plk1/phosphoinositide 3-kinase signaling pathways, in myelodysplastic syndrome. Other Plk inhibitors, including the Plk1 inhibitors GSK461364A, TKM-080301, GW843682, purpurogallin, and poloxin and the Plk4 inhibitor CFI-400945 fumarate, are in earlier clinical development. This review discusses the biologic roles of Plks in cell cycle progression and cancer, and the mechanisms of action of Plk inhibitors currently in development as cancer therapies. Copyright © 2015 The Author. Published by Elsevier Inc. All rights reserved.
    Translational oncology 06/2015; 9(3). DOI:10.1016/j.tranon.2015.03.010 · 2.88 Impact Factor
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    • "One of the possible implications of sustained production of high levels of ROS and RNS is oxidative stress-related deoxyribonucleic acid (DNA) damage (AshaRani et al., 2009; Schwartz and Rotter, 1998; Shackelford et al., 1999) and, accordingly, some reports in the literature have already shown that ION may induce DNA damage, namely Fe 2 O 3 nanoparticles (NP) in human lung fibroblasts IMR 90 cells (Bhattacharya et al., 2009, 2012) and oleate-coated Fe 3 O 4 NP in human peripheral lymphocytes (Magdolenova et al., 2013). In conditions of oxidative stress and/or in the presence of xenobiotics that cause DNA damage, cells have the ability to arrest cell cycle in G1 and G2 to allow adequate functioning of DNA repair systems and prevent the propagation of damage to the resulting daughter cells (AshaRani et al., 2009; Malumbres and Barbacid, 2009; Shackelford et al., 1999). Concerning ION, previous studies reported that g-Fe 2 O 3 NP and Fe 3 O 4 NP increase the proportion of cells in G1 phase of the cell cycle in RAW 264.7 cells (Park et al., 2014b), and in cells from the mouse bronchoalveolar lavage fluid (Park et al., 2010). "
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    ABSTRACT: The use of iron oxide nanoparticles (ION) for diagnostic and therapeutic purposes requires a clear favorable risk-benefit ratio. This work was performed with the aim of studying the ability of polyacrylic acid (PAA)-coated and non-coated ION to induce genotoxicity in human T lymphocytes. For that purpose, their influence on cell cycle progression and on the induction of chromosome aberrations was evaluated. Blood samples collected from healthy human donors were exposed to PAA-coated and non-coated ION, at different concentrations, for 48hours. The obtained results showed that, for all culture conditions, the tested ION are not genotoxic and do not influence the cell cycle arrest. Their possible cumulative effect with the iron-dependent genotoxic agent BLM was also evaluated. Blood samples collected from healthy human donors were exposed to ION, at different concentrations, for 48hours, in the presence of a pre-determined toxic concentration of BLM. The obtained results showed that, for all culture conditions, the tested ION do not potentiate the clastogenic effects of BLM. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Toxicology Letters 02/2015; 234(2). DOI:10.1016/j.toxlet.2015.02.010 · 3.26 Impact Factor
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    • "Cyclin/CDK complexes have important role in cellular signaling as well as cell proliferation [18]. The spleen tyrosine kinase (Syk) is involved in the signaling pathways in hematopoietic cells and is suggested to be a part of signaling in nonhematopoietic cell types as well [19] [20]. "
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    ABSTRACT: This study is done to evaluate the effect of spleen tyrosine kinase inhibitor (BAY 61-3606), cyclin-dependent kinase inhibitor (CDKi), and sodium butyrate (Na-Bu) on the level and phosphorylation of p53 protein and its binding to murine double minute 2 (MDM2) homologue in human vestibular schwannomas (VS). Primary cultures of the tumor tissues were treated individually with optimum concentrations of these small molecules in vitro. The results indicate modulation of p53 protein status and its binding ability to MDM2 in treated samples as compared to the untreated control. The three individual treatments reduced the level of total p53 protein. These treatments also decreased Ser392 and Ser15 phosphorylated p53 in tumor samples of young patients and Ser315 phosphorylated p53 in old patients. Basal level of Thr55 phosphorylated p53 protein was present in all VS samples and it remained unchanged after treatments. The p53 protein from untreated VS samples showed reduced affinity to MDM2 binding in vitro and it increased significantly after treatments. The MDM2/p53 ratio increased approximately 3-fold in the treated VS tumor samples as compared to the control. The differential p53 protein phosphorylation status perhaps could play an important role in VS tumor cell death due to these treatments that we reported previously.
    The Journal of cancer research 10/2014; DOI:10.1155/2014/249354
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