Table of Contents

Volume 8, Issue 5

  March 1, 2009

  Pages 675 - 791

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 Issue Catalogue (MARC XML)

NEWS & VIEWS

Open Access Article

Myeloid differentiation continues to reveal the complexity of nuclear receptor signaling

Moray J. Campbell
Pages 675 - 676
http://dx.doi.org/10.4161/cc.8.5.8182
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Open Access Article

REDD1, a new Ras oncogenic effector

Elizabeth R. Smith and Xiang-Xi Xu
Pages 675 - 676
http://dx.doi.org/10.4161/cc.8.5.8184
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EDITORIALS: CELL CYCLE FEATURES

Open Access Article

Pituitary adenoma growth: A model for cellular senescence and cytokine action

Eduardo Arzt, Vera Chesnokova, Günter K. Stalla and Shlomo Melmed
Pages 677 - 682
http://dx.doi.org/10.4161/cc.8.5.8065
Abstract | PDF

New findings have emerged about the mechanism of oncogene-induced senescence, and its involvement in a highly prevalent disorder, pituitary adenomas. These observations point to senescence as a target for effective therapy for both tumor silencing and growth restraint towards development of pituitary malignancy.

Open Access Article

Dual roles of topoisomerase II

Kuntian Luo and Zhenkun Lou
Pages 677 - 682
http://dx.doi.org/10.4161/cc.8.5.8070
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Open Access Article

Cell cycle arrest or apoptosis by p53: Are microRNAs-192/215 and -34 making the decision?

Sara A. Georges, B. Nelson Chau, Christian J. Braun, Xin Zhang and Matthias Dobbelstein
Pages 677 - 682
http://dx.doi.org/10.4161/cc.8.5.8076
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Open Access Article

On the robustness of mammalian circadian oscillators

Charna Dibner
Pages 677 - 682
http://dx.doi.org/10.4161/cc.8.5.8083
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EXTRA VIEWS

Open Access Article

MMP-2 functions as an early response protein in ovarian cancer metastasis

Hilary A. Kenny and Ernst Lengyel
Pages 683 - 688
http://dx.doi.org/10.4161/cc.8.5.7703
Abstract | PDF

The most common site (80%) of ovarian cancer metastasis is the omentum, a large (15x10x2cm) peritoneal fold covering the small bowel. Because of the absence of model systems that accurately reproduce the microenvironment of the human omentum, the biological mechanism of early ovarian cancer metastasis is poorly understood.  Using a new organotypic 3D culture of the omentum, we show that when cancer cells adhere, matrix-metalloproteinase (MMP) -2 is upregulated and proteolytically activated in these cells.  The activated MMP-2 cleaves the matrix proteins fibronectin, vitronectin, and collagen I into smaller fragments. The cleaved extra-cellular matrix (ECM) fragments then facilitate and accelerate cancer cell adhesion and invasion by binding to their cognate integrin receptors. In vivo inhibition of MMP-2 before adhesion by using a siRNA or a blocking antibody significantly reduced the number of metastasis and tumor weight in a xenograft mouse model. Blocking MMP-2 after metastasis had been established had no effect. Our data identify tumor-derived proteolytically active MMP-2 as an early regulator of ovarian cancer metastasis.

Open Access Article

Ubiquitination and deubiquitination of PCNA in response to stalling of the replication fork

Stephanie Brown, Atsuko Niimi and Alan R. Lehmann
Pages 689 - 692
http://dx.doi.org/10.4161/cc.8.5.7707
Abstract | PDF

Following exposure of human cells to DNA damaging agents that block the progress of the replication fork, mono-ubiquitination of PCNA mediates the switch from replicative DNA polymerases to polymerases specialised for translesion synthesis. We have shown that this modification of PCNA is necessary for the survival of cells after UV-irradiation and methyl methanesulfonate, that it is independent of cell cycle checkpoint activation, and that it persists after UV damage has been removed. In this Extra-view, we compare the regulation and biological significance of PCNA ubiquitination following treatments with UV light and the replication inhibitor hydroxyurea. We show that ubiquitination persists after removal of the replication block in both cases. With UV however, the persistence of ubiquitinated PCNA correlates with disappearance of the PCNA deubiquitinating enzyme USP1, whereas this is not the case for HU. Prevention of PCNA ubiquitination sensitises the cells to killing by both UV and HU.

Open Access Article

Cockayne Syndrome B protein (CSB): Linking p53, HIF-1 and p300 to robustness, lifespan, cancer and cell fate decisions

Mattia Frontini and Luca Proietti-De-Santis
Pages 693 - 696
http://dx.doi.org/10.4161/cc.8.5.7754
Abstract | PDF

Our recent data demonstrate that the CSB protein, besides its role in DNA repair, functions also as a master switch factor that can selectively influence the transcription of specific sets of genes, after DNA damage or hypoxia, by influencing the biological functions of p53. It is likely that the CSB protein, by modulating p53 activity after different cellular stresses would re-equilibrate the physiological response towards cell proliferation and survival instead of cell cycle arrest and cell death. Some important implications of these findings are discussed here.

Open Access Article

Trypanosome TOR complex 2 functions in cytokinesis

Antonio Barquilla and Miguel Navarro
Pages 697 - 699
http://dx.doi.org/10.4161/cc.8.5.7808
Abstract | PDF

TOR (target of rapamycin) is a kinase of the phosphatidylinositol kinase-related kinase (PIKK) family that controls cell growth in eukaryotes in response to nutrients, energy conditions, and growth factors. We have recently identified two trypanosome TOR orthologs, named TbTOR1 and TbTOR2, and two other proteins with significant homology to yeast or mammalian TORs, named TbTOR-like 1 and TbTOR-like 2. TbTOR1 depletion results in arrest of bloodstream trypanosomes in G1, concomitant to protein synthesis inhibition; however, TbTOR2 depletion leads to dramatic morphological defects in cell polarization, endocytosis, and cytokinesis. Rapamycin inhibits T. brucei cell growth by prevention of TORC2 complex formation, without any effect on TORC1 contrary to what generally occurs in other eukaryotes. Based on the unique features of T. brucei and its distal position in the eukaryotic cell lineage, we describe our views on the function of the TOR protein as a major regulator of cell growth and cytokinesis and discuss a possible role in the developmental differentiation processes.




PERSPECTIVES

Open Access Article

The multilayer regulation of the metaphase-to-anaphase transition

Fengzhi Jin, Daniel Richmond and Yanchang Wang
Pages 700 - 704
http://dx.doi.org/10.4161/cc.8.5.7678
Abstract | PDF

The fluctuating activity of the cyclin-dependent kinases (Cdks) is critical for the periodic phosphorylation of a given Cdk substrate. Previous studies have been focus on the positive role of Cdk-dependent protein phosphorylation in cell cycle progression. Recent studies indicate that, in budding yeast, highly active S-phase cyclin-associated Cdk not only promotes DNA synthesis but also inhibits the initiation of chromosome segregation. The FEAR (Cdc14 early anaphase release) pathway alleviates the negative effect of the S-phase cyclin on anaphase by promoting the dephosphorylation of S-phase cyclin-specific substrates, revealing a new layer of regulation in the metaphase-to-anaphase transition.

Open Access Article

Total ERK1/2 activity regulates cell proliferation

Renaud Lefloch, Jacques Pouysségur and Philippe Lenormand
Pages 705 - 711
http://dx.doi.org/10.4161/cc.8.5.7734
Abstract | PDF

Regulating ERK activity is essential for normal cell proliferation to occur. In mammals and most vertebrates ERK activity is provided by ERK1 and ERK2 that are highly similar, ubiquitously expressed and share activators and substrates. By combining single and double silencings of ERK1 and ERK2 we recently demonstrated that the apparent dominant role of ERK2 to regulate cell proliferation was due to its markedly higher expression level than ERK1. The contribution of ERK1 was revealed when ERK2 activation was clamped to avoid compensating over-activation of ERK2. We found no evidences in the literature for insulated isoform-specific modules in the Ras/Raf/MEK signaling cascade that could activate specifically ERK1 or ERK2. Obviously in frogs all signal integration and fine modulation provided by three Ras and three Raf isoforms is conducted by only one MEK and one ERK isoform. In mammals, ERK1 and ERK2 display similar specific activities and are activated respectively to their expression levels. After integrating signals from Ras, Raf and MEK isoforms, ERK1 and ERK2 regulate positively cell proliferation according to their expression levels.

Open Access Article

MiR-34, SIRT1, and p53: The feedback loop

Munekazu Yamakuchi and Charles J. Lowenstein
Pages 712 - 715
http://dx.doi.org/10.4161/cc.8.5.7753
Abstract | PDF

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression.  Several studies have linked dysregulation of miRNA with tumorigenesis.  The TP53 is one of the most commonly mutated genes in human cancers, and its gene product p53 activates transcription of a set of miRNA including the miR-34 family of miRNA.  The miR-34 family regulates cell cycle progression, cellular senescence, and apoptosis, but the targets of miR-34 are not completely defined.  We recently found that miR-34a inhibits SIRT1, a gene that regulates cellular senescence and limits longevity.   SIRT1 also regulates p53 dependent apoptosis through deacetylating and stabilizing p53.  We also discovered that SIRT1 mediates miR-34a activation of apoptosis by regulating p53 activity.  Based on this observation, we propose a positive feedback loop, in which p53 induces expression of miR-34a which suppresses SIRT1, increasing p53 activity.

Open Access Article

3D view to tumor suppression: lkb1, polarity and the arrest of oncogenic c-myc

Johanna I. Partanen, Anni I. Nieminen and Juha Klefstrom
Pages 716 - 724
http://dx.doi.org/10.4161/cc.8.5.7786
Abstract | PDF

Machiavelli wrote, in his famous political treatise Il Principe, about disrupting organization by planting seeds of dissension or by eliminating necessary support elements. Tumor cells do exactly that by disrupting the organized architecture of epithelial cell layers during progression from contained benign tumor to full-blown invasive cancer. However, it is still unclear whether tumor cells primarily break free by activating oncogenes powerful enough to cause chaos or by eliminating tumor suppressor genes guarding the order of the epithelial organization. Studies in Drosophila have exposed genes that encode key regulators of the epithelial apicobasal polarity and which, upon inactivation, cause disorganization of the epithelial layers and promote unscheduled cell proliferation. These polarity regulator/tumor suppressor proteins, which include products of neoplastic tumor suppressor genes (nTSGs), are carefully positioned in polarized epithelial cells to maintain the order of epithelial structures and to impose a restraint on cell proliferation. In this review, we have explored the presence and prevalence of somatic mutations in the human counterparts of Drosophila polarity regulator/tumor suppressor genes across the human cancers. The screen points out LKB1, which is a causal genetic lesion in Peutz-Jeghers cancer syndrome, a gene mutated in certain sporadic cancers and a human homologue of the fly polarity gene par-4. We review the evidence linking Lkb1 to polarity regulation in the scope of our recent results suggesting a coupled role for Lkb1 as an architect of organized acinar structures and a suppressor of oncogenic c-Myc. We finally present models to explain how Lkb1-dependent formation of epithelial architecture is coupled to suppression of normal and oncogene-induced proliferation.

Open Access Article

Nitric Oxide-mediated epigenetic mechanisms in developing neurons

Alexi Nott and Antonella Riccio
Pages 725 - 730
http://dx.doi.org/10.4161/cc.8.5.7805
Abstract | PDF

Epigenetic changes of chromatin are increasingly recognized as key modifications that dictate the differentiation state of cells during the development.  Within the central nervous system, extracellular cues induce chromatin remodelling events that are essential for neuronal progenitor proliferation, cell differentiation and, later, plasticity.  In this review, we discuss recent studies that show how extracellular and intranuclear signals influence chromatin remodelling and neuron-specific gene expression.  The gaseous molecule Nitric Oxide (NO) has recently emerged as a new key player that mediates the epigenetic changes associated with cell cycle arrest and differentiation in neurons.  Histone deacetylases (HDACs) are the first identified intranuclear targets of NO, but, due to its highly diffusible nature, it is likely that many other nuclear factors are directly regulated by NO.




REVIEW

Open Access Article

Epithelial ovarian cancer: Focus on genetics and animal models

Weiwei Shan and Jinsong Liu
Pages 731 - 735
http://dx.doi.org/10.4161/cc.8.5.7848
Abstract | PDF

Despite rapid advances in understanding ovarian cancer etiology, epithelial ovarian cancer remains the most lethal form of gynecologic cancers in the United States. The four morphologically-defined epithelial ovarian cancer subtypes–serous, endometrioid, mucinous, and clear cell carcinomas–are generally believed to originate from ovarian epithelial cells. Although it remains unclear how this single cell layer gives rise to morphologically distinct cancers, it has been suggested that early genetic events may direct the differentiation of ovarian epithelial cells. A number of genetic alterations are frequently encountered during ovarian tumorigenesis, including oncogenic activities of KRAS, BRAF, and AKT, and silencing mutations of TP53, RB, and PTEN. However, knowledge about how these genetic elements are coordinated during ovarian cancer initiation and progression is very limited. The establishment of cell-culture systems and rodent-based models has made big strides towards a better understanding of the genetic bases of human epithelial ovarian tumorigenesis. More importantly, the rise of genetically-engineered rodent and human models, particularly in the past five years, has provided key insight in the role of specific genes during ovarian tumorigenesis. In this review, we offer a comprehensive coverage of currently-available in vitro and in vivo models of human epithelial ovarian cancer, focusing on latest updates of genetically-modified rodent and human models and the valuable information conveyed by them.




REPORTS

Open Access Article

MicroRNAs181 regulate the expression of p27Kip1 in human myeloid leukemia cells induced to differentiate by 1,25-dihydroxyvitamin D3

Xuening Wang, Elzbieta Gocek, Chang-Gong Liu and George P. Studzinski
Pages 736 - 741
http://dx.doi.org/10.4161/cc.8.5.7870
Abstract | PDF

Human myeloid leukemia cells exposed to 1,25-dihydroxyvitamin D3 (1,25D), a major cancer chemopreventive agent, acquire features of normal monocytes and arrest in the G1 phase of the cell cycle, due to the upregulation of p27Kip1 and p21Cip1, but the mechanism is not clear. Here evidence is provided that an exposure of HL60 and U937 cells to low (1-10 nM) concentrations of 1,25D decreases the expression of miR181a and miR181b in a concentration and time-dependent manner. Since the predicted miR181 targets include the 3’-UTR of p27Kip1, we expressed pre-miR181a in these cells, and found that the elevation of cellular miR181a levels abrogates the 1,25D-induced increase in p27Kip1 at both mRNA and protein levels. In contrast, transfection of pre-miR181a resulted in a slight elevation of p21Cip1 expression. Importantly, transfection of pre-miR181a blunted the effect of 1,25D on the expression of monocytic differentiation markers, and reduced the G1 block in 1,25D-treated cells, while transfection of anti-miR181a increased 1,25D-induced differentiation. Together, these data show that miR181a participates in 1,25D-induced differentiation of HL60 and U937 cells, and suggest that a high constitutive expression of members of miR181 family may contribute to the malignant phenotype in the myeloid lineage.

Open Access Article

TGFβ prevents proteasomal degradation of the cyclin-dependent kinase inhibitor p27kip1 for cell cycle arrest

Jon Lecanda, Vidya Ganapathy, Christine D’Aquino-Ardalan, Brad Evans, Caprice Cadacio, Aidee Ayala and Leslie I. Gold
Pages 742 - 756
http://dx.doi.org/10.4161/cc.8.5.7871
Abstract | PDF

TGF-β mediates cell cycle arrest in late G1 phase with a simultaneous peak in the levels of the cyclin-dependent kinase inhibitor, p27kip1 (p27).  In this report, we show that whereas p27 resides in the cytoplasm in the endometrial carcinoma (ECA) cell line HEC-1A, TGF-β increases the total levels and translocation of p27 into the nucleus. Concomitantly, TGF-β activates the transcription factors Smad2 and Smad3, inhibits proliferation, and blocks Cdk2 activity; all these events are blocked by an inhibitor of TβRI serine kinase activity (SD208).  In addition, we show that inhibiting p27 transcription with a specific siRNA completely blocks TGF-β-mediated growth inhibition in these cells.  These data suggest that TGF-β inhibits cellular proliferation by increasing p27 levels through Smad2/3 signaling in HEC-1A cells.  We further show that TGF-β decreases the levels of components of the SCFSkp2 targeting complex for ubiquitin-mediated degradation of p27 in proteasomes, at the protein but not the mRNA level.  Therefore, TGF-β accumulates nuclear p27 by preventing its degradation to enable G1 arrest in HEC-1A cells.  Importantly, these data suggest a novel mechanism for TGF-β/Smad mediated growth inhibition that might be inoperable in the numerous human cancers demonstrating early dysregulated TGF¬-β signaling and loss of growth inhibition.  The TGF-β/p27 axis might provide novel therapeutic targets for cancer.

Open Access Article

The actin-binding and bundling protein, EPLIN, is required for cytokinesis

Megan Chircop, Vanessa Oakes, Mark E. Graham, Maggie P.C. Ma, Charlotte M. Smith, Phillip J. Robinson and Kum Kum Khanna
Pages 757 - 764
http://dx.doi.org/10.4161/cc.8.5.7878
Abstract | PDF

Cytokinesis involves two phases: 1) membrane ingression followed by 2) membrane abscission. The ingression phase generates a cleavage furrow and this requires co-operative function of the actin-myosin II contractile ring and septin filaments. We demonstrate that the actin-binding protein, EPLIN, locates to the cleavage furrow during cytokinesis and this is possibly via association with the contractile ring components, myosin II, and the septin, Sept2. Depletion of EPLIN results in formation of multinucleated cells and this is associated with inefficient accumulation of active myosin II (MRLCS19) and Sept2 and their regulatory small GTPases, RhoA and Cdc42, respectively, to the cleavage furrow during the final stages of cytokinesis. We suggest that EPLIN may function during cytokinesis to maintain local accumulation of key cytokinesis proteins at the furrow.

Open Access Article

Benzo[e]pyridoindoles,  novel inhibitors of the Aurora kinases

Thi My-Nhung Hoang, Bertrand Favier, Annie Valette, Caroline Barette, Chi Hung Nguyen, Laurence Lafanechère, David S. Grierson, Stefan Dimitrov and Annie Molla
Pages 765 - 772
http://dx.doi.org/10.4161/cc.8.5.7879
Abstract | PDF

Aurora kinases are serine/threonine protein kinases that are involved in cancer development and are important targets for cancer therapy. By high throughput screening of a chemical library we found that benzo[e]pyridoindole derivatives  inhibited Aurora kinase. The most potent compound (compound 1) was found to be an ATP competitive inhibitor, which inhibited in vitro Aurora kinases at the nanomolar range. It prevented, ex vivo, the phosphorylation of Histone H3, induced mitosis exit without chromosome segregation, known phenomena observed upon Aurora B inactivation. This compound was also shown to affect the localization of Aurora B, since in the presence of the inhibitor the enzyme was delocalized on the whole chromosomes and remained associated with the chromatin of newly formed nuclei.
In addition, compound 1 inhibited the growth of different cell lines derived from different carcinoma. Its IC50 for H358 NSCLC (Non Small Cancer Lung Cells), the most sensitive cell line, was 145 nM. Furthermore compound 1 was found to be efficient towards multicellular tumor spheroid growth. It exhibited minimal toxicity in mice while it had some potency towards aggressive NSCLC tumors. Benzo[e]pyridoindoles represent thus a potential new lead for the development of Aurora kinase inhibitors.

Open Access Article

Logic of a mammalian metabolic cycle: An oscillated NAD+/NADH redox signaling regulates coordinated histone expression and S-phase progression

Fa-Xing Yu, Ru-Ping Dai, Shuang-Ru Goh, Lei Zheng and Yan Luo
Pages 773 - 779
http://dx.doi.org/10.4161/cc.8.5.7880
Abstract | PDF

Many biological activities naturally oscillate.  Here, we show that the NAD+/NADH ratios (redox status) fluctuate during mammalian cell cycle, with the S-phase redox status being the least oxidative.  The S-phase NAD+/NADH redox status gates histone expression and S-phase progression, and may provide a genome protection mechanism during S-phase DNA replication as implicated in yeast.  Accordingly, perturbing the cellular redox inhibits histone expression and leads to S-phase arrest.  We propose that the S-phase NAD+/NADH redox status constitutes a redox signaling, which along with the cyclin E/cdk2 signaling regulates histone expression and S-phase progression.

Open Access Article

REDD1 is required for RAS-mediated transformation of human ovarian epithelial cells

Bin Chang, Guangzhi Liu, Gong Yang, Imelda Mercado-Uribe, Miao Huang and Jinsong Liu
Pages 780 - 786
http://dx.doi.org/10.4161/cc.8.5.7887
Abstract | PDF

REDD1 is a gene induced by hypoxia and stimuli from multiple DNA damage. Here we show that REDD1 expression was elevated in RAS-transformed ovarian epithelial cells lines and that this overexpression increased these cells’ growth rate and anchorage-independent growth on soft agar. Injection of immortalized ovarian epithelial cells overexpressing REDD1 into nude mice resulted in tumor growth that developed into papillary serous carcinoma in the peritoneal cavity. Knockdown of REDD1 expression blocked the RAS-mediated transformation of these cell lines. Apoptosis was markedly decreased by increased expression of Bcl-xL or Bcl-2 and  decreased expression of FADD, caspase1, caspase8, caspase 9, caspase 10, BAX, Bad and Bcl-Xs, which confirmed by the tunnel assay. Our data demonstrated that REDD1 is a key mediator in RAS-mediated transformation through an effect on anti-apoptosis.




LETTERS TO THE EDITOR

Open Access Article

Chromosome 1q gain is not associated with a poor outcome in childhood medulloblastoma: Requirements for the validation of potential prognostic biomarkers

Steven C. Clifford, Kieran O’Toole and David W. Ellison
Page 787
http://dx.doi.org/10.4161/cc.8.5.7709
PDF

Open Access Article

Mitotic kinase dynamics of the active form of AMPK (Phospho-AMPKαThr172) in human cancer cells

Alejandro Vazquez-Martin, Eugeni López-Bonet, Cristina Oliveras-Ferraros, Maria Carmen Pérez-Martínez, Luis Bernadó and Javier A. Menendez
Pages 788 - 791
http://dx.doi.org/10.4161/cc.8.5.7787
PDF