Cell cycle (Georgetown, Tex.) (CELL CYCLE)

Publications in this journal

• Article: LXCXE-independent chromatin remodeling by Rb/E2f mediates neuronal quiescence

  Andrusiak MG, Vandenbosch R, Dick FA, Park DS, Slack RS
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  ABSTRACT: Neuronal survival is dependent upon the retinoblastoma family members, Rb1 (Rb) and Rb2 (p130). Rb is thought to regulate gene repression, in part, through direct recruitment of chromatin modifying enzymes to its conserved LXCXE binding domain. We sought to examine the mechanisms that Rb employs to mediate cell cycle gene repression in terminally differentiated cortical neurons. Here, we report that Rb loss converts chromatin at the promoters of E2f-target genes to an activated state. We established a mouse model system in which Rb-LXCXE interactions could be induciblely disabled. Surprisingly, this had no effect on survival or gene silencing in neuronal quiescence. Absence of the Rb LXCXE-binding domain in neurons is compatible with gene repression and long-term survival, unlike Rb deficiency. Finally, we are able to show that chromatin activation following Rb deletion occurs at the level of E2fs. Blocking E2f-mediated transcription downstream of Rb loss is sufficient to maintain chromatin in an inactive state. Taken together our results suggest a model whereby Rb-E2f interactions are sufficient to maintain gene repression irrespective of LXCXE-dependent chromatin remodeling.
  Cell cycle (Georgetown, Tex.) 05/2013; 12(9).
• Article: LXCXE-independent chromatin remodeling by Rb/E2f mediates neuronal quiescence

  Matthew G. Andrusiak, Renaud Vandenbosch, Fred A. Dick, David S. Park, Ruth S. Slack
  Cell cycle (Georgetown, Tex.) 05/2013;
• Article: Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition.

  Bonora M, Bononi A, De Marchi E, Giorgi C, Lebiedzinska M, Marchi S, Patergnani S, Rimessi A, Suski JM, Wojtala A, Wieckowski MR, Kroemer G, Galluzzi L, Pinton P
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  ABSTRACT: The term "mitochondrial permeability transition" (MPT) refers to an abrupt increase in the permeability of the inner mitochondrial membrane to low molecular weight solutes. Due to osmotic forces, MPT is paralleled by a massive influx of water into the mitochondrial matrix, eventually leading to the structural collapse of the organelle. Thus, MPT can initiate mitochondrial outer membrane permeabilization (MOMP), promoting the activation of the apoptotic caspase cascade as well as of caspase-independent cell death mechanisms. MPT appears to be mediated by the opening of the so-called "permeability transition pore complex" (PTPC), a poorly characterized and versatile supramolecular entity assembled at the junctions between the inner and outer mitochondrial membranes. In spite of considerable experimental efforts, the precise molecular composition of the PTPC remains obscure and only one of its constituents, cyclophilin D (CYPD), has been ascribed with a crucial role in the regulation of cell death. Conversely, the results of genetic experiments indicate that other major components of the PTPC, such as voltage-dependent anion channel (VDAC) and adenine nucleotide translocase (ANT), are dispensable for MPT-driven MOMP. Here, we demonstrate that the c subunit of the FO ATP synthase is required for MPT, mitochondrial fragmentation and cell death as induced by cytosolic calcium overload and oxidative stress in both glycolytic and respiratory cell models. Our results strongly suggest that, similar to CYPD, the c subunit of the FO ATP synthase constitutes a critical component of the PTPC.
  Cell cycle (Georgetown, Tex.) 01/2013; 12(4).
• Article: p21CDKN1A does not interfere with loading of PCNA at DNA replication sites, but inhibits subsequent binding of DNA polymerase delta at the G1/S phase transition.

  Ornella Cazzalini, Paola Perucca, Federica Riva, Lucia A Stivala, Livia Bianchi, Vanio Vannini, Bernard Ducommun, Ennio Prosperi
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  ABSTRACT: The ability of the cyclin-dependent kinase (CDK) inhibitor p21CDKN1A to interact with PCNA recruited to DNA replication sites was investigated to elucidate the relevance of this interaction in cell cycle arrest. To this end, expression of p21 protein fused to green fluorescent protein (GFP) was induced in HeLa cells. G1 phase cell cycle arrest induced by p21GFP occurred also at the G1/S transition, as shown by cyclin A immunostaining of GFP-positive cells. Confocal microscopy analysis and co-immunoprecipitation studies showed that p21GFP co-localized and interacted with chromatin-bound PCNA and CDK2. GFP-p21 mutant forms unable to bind to PCNA (p21PCNA-) or CDK (p21CDK-) induced cell cycle arrest, although immunoprecipitation experiments showed these mutants to be unstable. Expression of HA-tagged p21wt or mutant proteins confirmed the ability of both mutants to arrest cell cycle. p21(wt)HA and p21CDK-HA, but not p21PCNA-, co-localized and co-immunoprecipitated with chromatin-bound PCNA. Association of p21 to chromatin-bound PCNA resulted in the loss of interaction with the p125 catalytic subunit of DNA polymerase delta (pol delta). These results suggest that in vivo p21 does not interfere with loading of PCNA at DNA replication sites, but prevents, or displaces subsequent binding of pol delta to PCNA at the G1/S phase transition.
  Cell cycle (Georgetown, Tex.) 01/2013; 2(6):596-603.
• Article: Inhibition of Cyclin d1 gene transcription by BRG1

  Rao M, Casimiro MC, Lisant MP, D'aminco M, shirley LA, Leader JE, Liu M, Stallcup M, Engel DA, Murphy DJ, Pestell RJ
  Cell cycle (Georgetown, Tex.) 01/2008; 5(7):647.
• Article: Stress signaling and Myc downregulation: implications for cancer.

  Zhongdong Huang
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  ABSTRACT: The transcription factor Myc forms a complex with its partner Max and with the regulatory DNA sequences on its target genes. Formation of this complex is required for Myc functions and Myc-induced oncogenic transformation. We have recently shown that formation of the Myc/Max/DNA complex is inhibited by the stress-responsive protein kinase Pak2 signaling pathway through phosphorylation of Myc. As a consequence of the phosphorylation, Myc loses its gene activation activity and the ability to induce proliferation and cellular transformation. Additionally, phosphorylation induces degradation of the Myc protein. Activation of stress signaling pathways, including Pak2 activity, may be a potential therapeutic approach to block Myc-induced neoplasia.
  Cell cycle (Georgetown, Tex.) 06/2004; 3(5):593-6.
• Source

  Available from: fly-bay.net

  Article: Pathways sufficient to induce epidermal carcinogenesis.

  Todd W Ridky, Paul A Khavari
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  ABSTRACT: Abnormal epidermal proliferation is characteristic of a number of disorders, including the two most common cancers in the United States, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Both cancers display a disruption in the normal homeostatic balance between cell division and programmed cell death. While abnormal activation of the sonic hedgehog/patched pathway has been established as sufficient to induce hallmark features of BCC in both human and murine epidermis, pathways sufficient to convert normal epidermis into SCC have been less well defined. Building on findings that indicate a potent role for Ras and NF-kappaB in normal epidermal growth regulation, recent work indicates that activation of Ras signaling in concert with inhibition of NF-kappaB function is entirely sufficient to transform normal human epidermis into tumor tissue with all the cardinal features of SCC.
  Cell cycle (Georgetown, Tex.) 06/2004; 3(5):621-4.
• Article: The mechanism of the anti-tumor activity of the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA).

  Paul A Marks
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  ABSTRACT: Histone deacetylases (HDAC) are ubiquitously distributed through chromatin. Nevertheless HDAC inhibitors (HDACi), such as SAHA, selectively alter the transcription of as few as 2-5% of expressed genes in various transformed cells. p21(WAF1) is one of the most commonly induced genes in cells cultured with SAHA. Understanding the mechanism of the selective effects of the HDACi is a challenging problem. Gui et al. have identified effects of SAHA on p21(WAF1) promotor associated proteins that explain, at least in part, the selective effects of HDAC in altering gene expression.
  Cell cycle (Georgetown, Tex.) 06/2004; 3(5):534-5.
• Article: The toposome: a new twist on topoisomerase IIalpha.

  James A Borowiec
  Cell cycle (Georgetown, Tex.) 06/2004; 3(5):627-8.
• Source

  Available from: fly-bay.net

  Article: Inhibition of Chk1 by activated PKB/Akt.

  Frank W King, Jennifer Skeen, Nissim Hay, Emma Shtivelman
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  ABSTRACT: We have shown recently that DNA damage effector kinase Chk1 is phosphorylated in vitro by protein kinase B/Akt (PKB/Akt) on serine 280. Activation of Chk1 by DNA damage in vivo is suppressed in presence of activated PKB. In this study we show that Chk1 is phosphorylated by PKB in vivo, and that increased phosphorylation by PKB on serine 280 correlates with impairment of Chk1 activation by DNA damage. Our results indicate a likely mechanism for the negative effects that phosphorylation of serine 280 has on activation of Chk1. The Chk1 protein phosphorylated by PKB on serine 280 does not enter into protein complexes after replication arrest. Moreover, Chk1 phosphorylated by PKB fails to undergo activating phosphorylation on serine 345 by ATM/ATR. Phosphorylation by ATM/ATR and association with other checkpoint proteins are essential steps in activation of Chk1. Inhibition of these steps provides a plausible explanation for the observed attenuation of Chk1 activation by activated PKB after DNA damage.
  Cell cycle (Georgetown, Tex.) 06/2004; 3(5):634-7.
• Article: Cycling without the cyclosome: modeling a yeast strain lacking the APC.

  Brian R Thornton, Katherine C Chen, Frederick R Cross, John J Tyson, David P Toczyski
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  ABSTRACT: The construction of viable Saccharomyces cerevisiae strains that lack the anaphase promoting complex (APC) was recently reported. The normally lethal deletions of APC genes were suppressed by the double deletion of the PDS1 and CLB5 genes in conjunction with the insertion of multiple copies of the SIC1 gene controlled by its endogenous promoter. It was proposed that cyclic expression and degradation of Sic1 results in oscillations of Clb/CDK activity necessary for the cell cycle. We have used an updated version of a mathematical model of the yeast cell cycle to model strains that lack the APC. With a few modifications, the model accurately simulates the viability of Apc- strains, as well as the phenotypes of 27 other previously characterized strains. We discuss a few minor inconsistencies between the model and experiment, and how these may inform future revisions to the model.
  Cell cycle (Georgetown, Tex.) 06/2004; 3(5):629-33.
• Source

  Available from: kelly-landes.org

  Article: Model predictions of MDM2 mediated cell regulation.

  Mandri N Obeyesekere, Edwin Tecarro, Guillermina Lozano
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  ABSTRACT: In this work we present a mathematical approach to elucidate possible mechanisms involving mdm2 in the regulation of the cell cycle. It has been experimentally shown that the over-expression of MDM2 leads to decoupling of DNA synthesis with mitosis resulting in polyploidy cells with multiple copies of their genomes. The function of MDM2 that uncouples the DNA synthesis phase (S) and the Mitosis phase (M) is unclear. To answer this question, we first formulate a mathematical model of the dynamics of the cell cycle regulatory proteins during the DNA synthesis phase and mitosis. This model is then tested for bifurcation that produces period doubling cascades that we relate to the biological event of polyploidy. The model formulation, the underlying biology, and the bifurcation results to delineate the unknown function of MDM2 are presented. Based on reproducing known experimental result of polyploidy in MDM2 overexpressed cells, we propose several possible functions of mdm2, i.e., possible interactions with the other cell cycle regulating proteins that will result in uncoupling the S and M phases. We conclude that the most likely unknown function of MDM2 leading to the decoupling of the S and M phases is an obstruction of the activation of Cdc25C by MDM2.
  Cell cycle (Georgetown, Tex.) 06/2004; 3(5):655-61.
• Source

  Available from: psychepharmaceuticals.com

  Article: Oncogenic K-ras in mouse models of myeloproliferative disease and acute myeloid leukemia.

  Iris T Chan, D Gary Gilliland
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  ABSTRACT: Oncogenic N-RAS and K-RAS mutations are among the most frequently detected genetic alterations in patients with acute myeloid leukemia (AML). Recently, the role of oncogenic K-ras in leukemogenesis was investigated in a novel mouse model utilizing interferon (IFN)-inducible, Cre-mediated expression of oncogenic K-ras from its endogenous promoter. Conditional expression of oncogenic K-ras from its endogenous promoter in the hematopoietic system induces a lethal myeloproliferative disease in mice, but not AML, indicating that additional mutations are required for AML development. These results are consistent with a model in which the AML phenotype requires at least two cooperating mutations in the hematopoietic progenitor cells: one promoting proliferation and enhanced cell survival (such as oncogenic ras or a constitutively activated receptor tyrosine kinase) and one associated with impaired differentiation and enhanced immortalization (such as loss-of-function mutations in hematopoietic transcription factors). The model system with oncogenic K-ras provides a versatile platform to test the contribution of cooperating mutations in AML, and the efficacy of Ras pathway inhibitors in vivo.
  Cell cycle (Georgetown, Tex.) 06/2004; 3(5):536-7.
• Source

  Available from: orphanresearch.com

  Article: Control of tumor suppressor p53 function by endoplasmic reticulum stress.

  Like Qu, Antonis E Koromilas
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  ABSTRACT: Alterations in the homeostasis of the endoplasmic reticulum (ER) by various forms of stress can lead to the accumulation of unfolded proteins and protein aggregates that are detrimental to cell survival. Eukaryotic cells can adapt to ER stress by activating specific signaling pathways and mechanisms, whose primary purpose is to limit the accumulation of unfolded proteins in the ER. We recently reported a novel mechanism of cell adaptation to ER stress, which proceeds through the inhibition of the apoptotic function of the tumor suppressor p53 (Genes Dev 2004;18:261-277). We found that ER stress increases the cytoplasmic localization and enhances the destabilization of the tumor suppressor. This process requires the phosphorylation of p53 at serine 315 and serine 376, which is mediated by the activation of glycogen synthase kinase-3beta (GSK-3beta). ER stress also prevents p53 activation and p53-mediated apoptosis in response to DNA damage. These findings demonstrate that ER stress utilizes mechanisms that are distinct from other types of stress to modulate p53. In addition, they reveal that ER stress and nuclear DNA damage can induce inter-organellar cross-talk pathways targeting p53 with important implications for the treatment of tumors with dysfunctional ER.
  Cell cycle (Georgetown, Tex.) 06/2004; 3(5):567-70.
• Article: Cyclin D/Cdk4: new insights from Drosophila.

  Christian Frei
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  ABSTRACT: The Drosophila cyclin-dependent protein kinase complex CycD/Cdk4 has been known to drive cellular growth (accumulation of mass) as well as proliferation (cell cycle progression). Recent data demonstrate that Hif prolyl hydroxylase (Hph) is required for the induction of growth, but not for the induction of proliferation. Normal levels of Hph are required for cellular growth, demonstrating that Hph, in addition to its known function in the cellular response low oxygen levels, regulates growth. Since Hph's hydroxylation activity depends on oxygen and possibly the mitochondrial activity, these data provide a link between CycD/Cdk4 and oxygen/energy homeostasis.
  Cell cycle (Georgetown, Tex.) 06/2004; 3(5):558-60.