Table of Contents

Volume 6, Issue 13

  July 1, 2007

  Pages 1533 - 1670

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 Issue Catalogue (MARC XML)

EXTRA VIEWS

Open Access Article

ALK is a Novel Dependence Receptor: Potential Implications in Development and Cancer

Michèle Allouche
Pages 1533 - 1538
http://dx.doi.org/10.4161/cc.6.13.4433
Abstract | PDF

ALK (anaplastic lymphoma kinase) is a transmembrane receptor tyrosine kinase, initially discovered as part of the NPM-ALK fusion protein, resulting from a chromosomal rearrangement frequently associated with anaplastic large cell lymphomas. The native ALK protein is normally expressed in the developing and, at a weaker level, adult nervous system. We recently demonstrated that ALK is a novel dependence receptor. As such, in the absence of ligand, the ALK receptor is kinase inactive and its expression results in enhanced apoptosis, whereas kinase activation, due to a ligand or constitutive as in NPM-ALK, decreases apoptosis. Unligated/kinase unactivated ALK receptor facilitates apoptosis via its own cleavage by caspases, a phenomenon allowing the exposure of a proapoptotic juxta-membrane intra-cellular domain. This review summarizes the biological significance of the ALK receptor in cancer and development, in perspective with its dependence receptor function. The dual function of ALK in the physiology of development is illustrated in the visual system of Drosophila. In this part of the nervous system, ALK in the presence of ligand appears essential for axonal guidance, whereas in the absence of ligand, ALK expression can lead to developmental neuronal apoptosis. ALK is also found expressed in neural crest-derived tumors such as human neuroblastomas or glioblastomas but its role is not fully elucidated. However, an excessive or constitutive ALK tyrosine kinase activation can lead to deregulation of cell proliferation and survival, therefore to human cancers such as lymphomas and inflammatory myofibroblastic tumors. Our observations could have important implications in the therapy of ALK-positive tumors harboring the chimeric or wild type ALK protein.

Open Access Article

MAPK- Kinases as Nucleo-Cytoplasmic Shuttles for PPARγ

Elke Burgermeister and Rony Seger
Pages 1539 - 1548
http://dx.doi.org/10.4161/cc.6.13.4453
Abstract | PDF

Peroxisome proliferator-activated receptor-gamma (PPARγ) is a ligand-activated transcription factor of the nuclear receptor superfamily that regulates genes involved in differentiation, metabolism and immunity. PPARγ-ligands are used for therapy of type 2 diabetes and hold the promise for treatment of inflammation and cancer. As a central regulatory component, PPARγ activity is well regulated during various cellular processes, and indeed mitogenic stimulation often suppresses PPARγ’s genomic activity. This down-regulation is mediated largely by the extracellular signal-regulated kinase 1/2 (ERKs)/mitogen-activated protein kinases (MAPKs) signaling cascade, which attenuates PPARγ’s transactivation function either by an inhibitory phosphorylation or by modulating PPARγ’s nucleo-cytoplasmic compartmentalization. The latter is achieved by the mitogen-induced nuclear export of PPARγ through its direct interaction with the ERK cascade component MAPK/ERK-kinases 1/2 (MEKs). Upon mitogenic stimulation, MEKs translocate into the nucleus, but are rapidly exported from this location by their N-terminal nuclear export signal (NES), in a process that is accompanied by the export of their interacting nuclear PPARγ molecules. Interestingly, it was recently demonstrated that PPARγ has cytoplasmatic activities, and therefore, the MEK-dependent shuttle may also represent a mechanism for control of the extra-nuclear/non-genomic actions of PPARγ. Because of the similarity within nuclear receptor docking motifs, it is possible that the same mechanism may control the nuclear and cytoplasmatic activity of other receptors. The changes in the subcellular localization of PPARγ may also represent novel targets for selective interference in patients with chronic inflammatory or proliferation-related diseases.

Open Access Article

Cdt1 Interactions in the Licensing Process: A Model for Dynamic Spatio-temporal Control of Licensing

Georgia Xouri, Maria Dimaki, Philippe I.H. Bastiaens and Zoi Lygerou
Pages 1549 - 1552
http://dx.doi.org/10.4161/cc.6.13.4455
Abstract | PDF

Within each cell cycle, a cell must ensure that the processes of selection of replication origins (licensing) and initiation of DNA replication are well coordinated to prevent re-initiation of DNA replication from the same DNA segment during the same cell cycle. This is achieved by restricting the licensing process to G1 phase when the prereplicative complexes (preRCs) are assembled onto the origin DNA, while DNA replication is initiated only during S phase when de novo preRC assembly is blocked. Cdt1 is an important member of the preRC complex and its tight regulation through ubiquitin-dependent proteolysis and binding to its inhibitor Geminin ensure that Cdt1 will only be present in G1 phase, preventing relicensing of replication origins. We have recently reported that Cdt1 associates with chromatin in a dynamic way and recruits its inhibitor Geminin onto chromatin in vivo. Here we discuss how these dynamic Cdt1-chromatin interactions and the local recruitment of Geminin onto origins of replication by Cdt1 may provide a tight control of the licensing process in time and in space.

Open Access Article

Shh Signaling and Pancreatic Cancer: Implications for Therapy?

Jennifer P. Morton and Brian C. Lewis
Pages 1553 - 1557
http://dx.doi.org/10.4161/cc.6.13.4467
Abstract | PDF

Hedgehog signaling has been implicated in the development of several human cancers, including small cell lung carcinomas, medulloblastomas, basal cell carcinomas, and digestive tract tumors. Elevated levels of pathway components are observed in pancreatic ductal adenocarcinoma (PDAC) precursor lesions, and these levels increase further as lesions progress to more advanced stages. Yet the mechanisms by which hedgehog signaling contributes to pancreatic tumorigenesis were poorly understood. We recently published results showing that activated hedgehog signaling enhances the proliferation and survival of pancreatic duct epithelial cells, the presumptive target cells for PDAC development. We also demonstrated that sonic hedgehog (Shh) expression, in cooperation with loss of the Trp53 and Ink4a/Arf tumor suppressor loci, was sufficient to initiate the formation of early pancreatic lesions. Furthermore, Shh signaling enhanced K-Ras-mediated pancreatic tumorigenesis and reduced the dependence of tumor cells on the sustained activation of Ras-stimulated signaling pathways. Here we discuss the significance of these findings and the implications for therapy.




PERSPECTIVES

Open Access Article

Detection and Correction of Merotelic Kinetochore Orientation by Aurora B and its Partners

Daniela Cimini
Pages 1558 - 1564
http://dx.doi.org/10.4161/cc.6.13.4452
Abstract | PDF

Merotelic kinetochore orientation is a kinetochore-microtubule mis-attachment in which a single kinetochore binds microtubules to both spindle poles, rather than just one. Merotelic attachments occur frequently in early mitosis and can induce anaphase lagging chromosomes and aneuploidy if not corrected before anaphase onset. Merotelic kinetochore orientation does not interfere with chromosome alignment at the metaphase plate and does not activate the mitotic spindle checkpoint. However, a correction mechanism for merotelic attachment reduces the number of merotelic kinetochores entering anaphase, thus preventing chromosome mis-segregation. Result from many different studies support the idea that Aurora B kinase plays a critical role in this merotelic correction mechanism by phosphorylating key substrates at the kinetochore and promoting turnover of kinetochore microtubules. In addition, recent studies are starting to identify the possible ‘sensors’ of the system that would be able to detect the mis-attachment and communicate this to Aurora B. Here, I review these studies and discuss a model for how merotelic kinetochore orientation could be detected and corrected before anaphase onset.

Open Access Article

Calcium Signals Induce Liver Stem Cells to Acquire a Cardiac Phenotype

Page A.W. Anderson, Barbara J. Muller-Borer, Gwyn L. Esch, William B. Coleman, Joe W. Grisham and Nadia N. Malouf
Pages 1565 - 1569
http://dx.doi.org/10.4161/cc.6.13.4454
Abstract | PDF

Heart failure is a major cause of premature death and disability in the United States. Stem cell therapy has attracted great interest for the treatment of myocardial infarction and heart failure. Some tissue-specific adult-derived stem cells demonstrate plasticity in that they are multipotent, react to inductive signals provided by a new micro-environment, and acquire the phenotype of cells endogenous to the new micro-environment. The mechanism through which this phenotype is acquired is unknown. We have demonstrated that a liver-derived clonal stem cell line, WB F344, differentiate into cardiomyocytes in vivo and in vitro. Using a co-culture model of neonatal heart cells and WB F344 cells, we have found that cytosolic communication between the two cell types results in calcium-induced transcription of cardiac transcription factors and appears to usher in the cardiac phenotype. Functional gap junctions and IP3 receptors appear to be required for this process. We propose that the observed low frequency of stem cell differentiation into cardiomyocytes when transplanted into the injured heart is due, in part, to their inability to establish functioning intercellular communications with healthy cardiomyocytes and receive instructive signals needed to activate a cardiac gene program.

Open Access Article

Gain of Function of p53 Cancer Mutants in Disrupting Critical DNA Damage Response Pathways

Hoseok Song and Yang Xu
Pages 1570 - 1573
http://dx.doi.org/10.4161/cc.6.13.4456
Abstract | PDF

Loss of the tumor suppression activity of p53 is required for the progression of most human cancers. In this context, p53 gene is somatically mutated in about half of all human cancers; in the rest human cancers, p53 is mostly inactivated due to the disruption of pathways important for its activation. Most p53 cancer mutations are missense mutations within the core domain, leading to the expression of full-length mutant p53 protein. The expression of p53 mutants is usually correlated with the poor prognosis of the cancer patients. Accumulating evidence has indicated that p53 cancer mutants not only lose the tumor suppression activity of WT p53, but also gain novel oncogenic activities to promote tumorigenesis and drug resistance. Therefore, to improve current cancer therapy, it is critical to elucidate the gain-of-functions of p53 cancer mutants. By analyzing the humanized p53 mutant knock-in mouse models, we have identified a new gain of function of the common p53 cancer mutants in inducing genetic instability by disrupting ATM-mediated cellular responses to DNA double-stranded break (DSB) damage. Considering that some current cancer therapies such as radiotherapy kills the cancer cells by inducing DSBs in their genome DNA, our findings will have important implications on the treatment of human cancers that express common p53 mutants.

Open Access Article

Rethinking the Mitochondrial Theory of Aging: The Role of Mitochondrial Gene Expression in Lifespan Determination

Nicholas D. Bonawitz and Gerald S. Shadel
Pages 1574 - 1578
http://dx.doi.org/10.4161/cc.6.13.4457
Abstract | PDF

The Mitochondrial Theory of Aging postulates that accumulation of mtDNA mutations and mitochondrial dysfunction are responsible for generating aging phenotypes and limiting lifespan. Although widely accepted, this theory remains unproven because the evidence supporting it, while substantial, is largely correlative. Furthermore, recent experimental results in mice with accelerated rates of mtDNA mutagenesis have challenged the traditional formulation of the Mitochondrial Theory, perhaps warranting a reevaluation of some of its core principles. In this perspective, we summarize recent work suggesting that both the quantity and the quality of mitochondrial gene expression play a much greater role in the aging process than previously appreciated. We speculate that this form of mitochondrial dysfunction may operate independently or in concert with mtDNA mutations to promote age-related pathology and limit lifespan.




PRIORITY REPORTS

Open Access Article

Shugoshin 1 Plays a Central Role in Kinetochore Assembly and is Required for Kinetochore Targeting of Plk1

Jeroen Pouwels, Anu M. Kukkonen, Weijie Lan, John R. Daum, Gary J. Gorbsky, P. Todd Stukenberg and Marko J. Kallio
Pages 1579 - 1585
http://dx.doi.org/10.4161/cc.6.13.4442
Abstract | PDF

Physical connection between the sister chromatids is mediated by the cohesin protein complex. During prophase, cohesin is removed from the chromosome arms while the centromeres remain united. Shugoshin1 (Sgo1) is required for maintenance of centromeric cohesion from prophase to the metaphase-anaphase transition. Furthermore, Sgo1 has been proposed to regulate kinetochore microtubule stability and sense interkinetochore tension, two tasks which are tightly coupled with the function of the Chromosomal Passenger Complex (CPC) and Polo-like kinase 1 (Plk1). Here we show that depletion or chemical inhibition of Aurora B kinase (AurB), the catalytic subunit of the CPC, disrupts accumulation of Sgo1 on the kinetochores in HeLa cells and causes Sgo1 to localize on the chromosome arms. RNAi assays show that depletion of Sgo1 did not affect AurB localization but diminished Plk1 kinetochore binding. Furthermore, we demonstrate that vertebrate Sgo1 is phosphorylated by both AurB and Plk1 in vitro. The data presented here includes an extensive analysis of kinetochore targeting interdependencies of mitotic proteins that propose a novel branch in kinetochore assembly where Sgo1 and Plk1 have central roles. Furthermore our studies implicate Sgo1 in the tension sensing mechanism of the spindle checkpoint by regulating Plk1 kinetochore affinity.

Open Access Article

Differential Regulation of microRNAs by p53 Revealed by Massively Parallel Sequencing: miR-34a is a p53 Target That Induces Apoptosis and G1-arrest

Valery Tarasov, Peter Jung, Berlinda Verdoodt, Dmitri Lodygin, Alexey Epanchintsev, Antje Menssen, Gunter Meister and Heiko Hermeking
Pages 1586 - 1593
http://dx.doi.org/10.4161/cc.6.13.4436
Abstract | PDF

In a genome‑wide screen for microRNAs regulated by the transcription factor encoded by the p53 tumor suppressor gene we found that after p53‑activation the abundance of thirty-four miRNAs was significantly increased, whereas sixteen miRNAs were suppressed. The induction of miR‑34a was most pronounced among all differential regulations. Also expression of the primary miR‑34a transcript was induced after p53 activation and by DNA damage in a p53‑dependent manner. p53 occupied an evolutionarily conserved binding site proximal to the first non-coding exon of miR‑34a. Ectopic miR‑34a induced apoptosis and a cell cycle arrest in the G1-phase, thereby suppressing tumor cell proliferation. Other p53‑induced miRNAs identified here may also have tumor suppressive potential as they are known to suppress the anti‑apoptotic factor Bcl2 (miR‑15a/16) and the oncogenes RAS and HMGA2 (let‑7a). Our results for the first time directly integrate the regulation of miRNA expression into the transcriptional network regulated by p53. siRNAs corresponding to p53‑induced miRNAs may have potential as cancer therapeutic agents as RNA interference based therapies are currently emerging.




REPORTS

Open Access Article

Differential Repression of c-myc and cdc2 Gene Expression by ERF and PE-1/METS

Kelly D. Hester, Dominique Verhelle, Laure Escoubet-Lozach, Rosa Luna, David W. Rose and Christopher K. Glass
Pages 1594 - 1604
http://dx.doi.org/10.4161/cc.6.13.4336
Abstract | PDF

The molecular mechanisms that control the proliferation and differentiation of specific cell types remain poorly understood. Positive ETS factors play important roles in mediating proliferative responses to Ras/MAPK signaling in many cell types following mitogenic stimulation. PE-1/METS, a member of the ETS-domain family transcription factors that functions as a transcriptional repressor, can block mitogenic responses mediated by positively acting Ets factors. The anti-proliferative functions of PE-1/METS require its interaction with DP103, a multifunctional DEAD-box protein that mediates interactions with co-repressor proteins and acts in a cooperative manner with Rb family members and to repress cell cycle control genes. ETS-2 Repressor Factor (ERF) is structurally related to and also functions as a transcriptional repressor, but endogenous target genes and mechanisms of repression remain unknown. Here, we demonstrate that like PE-1/METS, ERF-mediated repression also requires DP103, and that ERF negatively regulates the c-myc and cdc2 genes. In contrast to PE-1/METS, however, ERF-mediated repression of these genes is inactivated by MAPK signaling through phosphorylation sites that are ERF-specific. Furthermore, constitutive activation of the Ras/MAPK pathway in RAW 264.7 cells transformed by the v-Abelson leukemia virus is associated with constitutive inactivation of ERF in this cell type. We propose that ERF and PE-1/METS function to impose ‘repression checkpoints’ on a subset of cell cycle control genes that are differentially regulated by growth factor signaling pathways that control proliferation and differentiation and that ERF is targeted for inactivation by transforming oncogenes such as vAbl.

Open Access Article

ASPM and Citron Kinase Co-Localize to the Midbody Ring during Cytokinesis

Murugan Paramasivam, YoonJeung Chang and Joseph J. LoTurco
Pages 1605 - 1612
http://dx.doi.org/10.4161/cc.6.13.4356
Abstract | PDF

Mutations in ASPM (abnormal spindle-like microcephaly associated) and Citron Kinase (CITK) cause primary microcephaly in humans and rodents, respectively. Both proteins are expressed during neurogenesis and play important roles in neuronal progenitor cell division. ASPM is localized to the spindle pole, and is essential for maintaining proliferative cell division. CITK is present at the cytokinesis furrow and midbody ring, and it is essential for cellular abscission. We report here that ASPM also localizes to the midbody ring in mammalian cells. ASPM co-localizes with CITK at the midbody ring and co-immunoprecipitates with CITK in lysates prepared from HeLa cells and embryonic neuroepithelium. Furthermore, a GFP-tagged fragment of the N-terminus of ASPM localizes to centrosomes and spindle poles, while a GFP-tagged fragment of the C-terminus localizes to midbodies. All reported ASPM mutations that cause microcephaly involve a truncation or mutation of the C-terminus. In addition, at least two other microcephaly-related proteins, CENPJ and CDK5RAP2, previously localized to spindle poles, also localize to midbodies. Together our observations support a model of neurogenesis in which spindle dynamics and cellular abscission are coordinated.

Open Access Article

Cytoplasmic Volume Condensation Is an Integral Part of Mitosis

Christa W. Habela and Harald Sontheimer
Pages 1613 - 1620
http://dx.doi.org/10.4161/cc.6.13.4357
Abstract | PDF

Cell growth and osmotic volume regulation are undoubtedly linked to the progression of the cell cycle as with each division, a newly generated cell must compensate for loss of half of its volume to its sister cell. The extent to which size influences cell cycle decisions, however, is controversial in mammalian cells. Further, a mechanism by which cells can monitor and therefore regulate their size has not been fully elucidated. Despite an ongoing debate, there have been few studies which directly address the question in single cell real-time experiments. In this study we used fluorescent time-lapse imaging to quantitatively assess volume in individual spontaneously dividing cells throughout the cell cycle. Together with biophysical studies, these establish that the efflux of salt and water brings about a condensation of cytoplasmic volume as glioma cells progress through mitosis. As cells undergo this pre-mitotic condensation (PMC) they approach a preferred cell volume preceding each division. This is functionally linked to chromatin condensation, suggesting that PMC plays an integral role in mitosis.

Open Access Article

A Novel Cell Cycle Inhibitor Stalls Replication Forks and Activates S Phase Checkpoint

Vaidehi Krishnan, Léon Dirick, Hong Hwa Lim, Tiffany Siew Joo Lim, San Ling Si-Hoe, Chee Seng Cheng, Kai Lee Yap, Anthony Ting, Etienne Schwob and Uttam Surana
Pages 1621 - 1630
http://dx.doi.org/10.4161/cc.6.13.4373
Abstract | PDF

DNA replication checkpoint is activated in response to replication stresses. It maintains the integrity of stalled replication forks and prevents premature segregation of largely unreplicated chromosomes. In budding yeast, Mec1 and Rad53 kinases (homologous to mammalian ATM/ATR and Chk2 kinases, respectively) are the main effectors of this checkpoint control. Using a yeast based screen, we have identified a compound (named here ENA) which inhibits DNA replication and activates Mec1/Rad53 checkpoint. A brief exposure to this compound stops fork progression at or near replication origin and renders the forks incompetent to resume replication despite the presence of a functional checkpoint. ENA also inhibits DNA synthesis in mammalian cells leading to the activation of ATM/ATR pathway and the induction of apoptosis in a p53 independent manner. Interestingly, ENA acts as an effective antiproliferative agent against a subset of cancer cell lines and as an anti-tumor agent against human xenografts in mice. Thus, ENA is a potent cell cycle inhibitor with conceivable therapeutic potential.

Open Access Article

Linking Hepatic Transcriptional Changes to High–Fat Diet Induced Physiology for Diabetes-Prone and Obese-Resistant Mice

Ilias Alevizos, Jatin Misra, John Bullen, Giuseppe Basso, Joanne Kelleher, Christos Mantzoros and Gregory Stephanopoulos
Pages 1631 - 1638
http://dx.doi.org/10.4161/cc.6.13.4380
Abstract | PDF

Insulin resistance is characterized by high insulin levels and decreased responsiveness of tissues to the clearance of glucose from the bloodstream. This study maintained the diabetes-prone C57BL/6J and obese-resistant A/J mice strains on a high-fat diet for 12 weeks to transcriptionally profile the liver for changes caused by high fat diet. In the 8th week of the experiment, the C57BL/6J mice began exhibiting signs of insulin resistance, while the A/J mice did not show any such indications during the course of the experiment. A regression model of partial least squares between serum insulin measurements and the liver gene expression profile for the C57BL/6J mice on a high-fat diet was constructed in an effort to quantitatively link the physiological measurement with the gene expressions. A series of discriminating genes between high fat and chow fed mice was generated for both the C57BL/6J and A/J strains. These discriminatory genes contain information about the mechanisms responsible for the development of insulin resistance, and the compensation for a high fat diet, respectively. The results identified several genes involved in the development of insulin resistance and serve as a framework for other studies involving other organs affected by this systemic disease.

Open Access Article

Different Thresholds of MPF Inactivation are Responsible for Controlling Different Mitotic Events in Mammalian Cell Division

Naihan Xu and Donald C. Chang
Pages 1639 - 1645
http://dx.doi.org/10.4161/cc.6.13.4385
Abstract | PDF

We present evidence for a paradigm that, during cell division, the decreasing activity of MPF acts as a master signal, which utilizes different thresholds to control the initiation of different mitotic events. The key temporal control here is the degradation of cyclin B1. Using single cell analysis, we measured the kinetics of cyclin B1 degradation and determined quantitatively the thresholds of cyclin B1 level for different mitotic events within a HeLa cell. These observed thresholds were: 1.36 ± 0.49 μM (for chromosome separation), 0.75 ± 0.08 μM (for cytokinesis) and 0.54 ± 0.16 μM (for nuclear reassembly). By comparison, the average concentration of endogenous cyclin B1 within a prometaphase cell was found to be 2.92 ± 1.7 μM. We suggest that the decreasing order of these thresholds plays an important role in triggering the initiation of successive mitotic events in cell division.

Open Access Article

Loss of ChlR1 Helicase in Mouse Causes Lethality Due to the Accumulation of Aneuploid Cells Generated by Cohesion Defects and Placental Malformation

Akira Inoue, Tongyuan Li, Sarah K. Roby, Marcus B. Valentine, Madoka Inoue, Kelli Boyd, Vincent J. Kidd and Jill M. Lahti
Pages 1646 - 1654
http://dx.doi.org/10.4161/cc.6.13.4411
Abstract | PDF

Human DDX11 and DDX12 are closely related genes encoding the helicases ChlR1 and ChlR2, which belong to the CHL1 DNA helicase family. Recently, it was shown that human ChlR1 interacts with components of the cohesin complex and is required for proper centromeric cohesion. To establish the function of ChlR1 in development we made a mutant mouse lacking Ddx11, the single mouse ChlR gene. The absence of Ddx11 resulted in embryonic lethality at E10.5. The mutant embryos were smaller in size, malformed and exhibited sparse cellularity in comparison to normal or heterozygous litter mates. Importantly, loss of Ddx11 resulted in the inability to form a proper placenta, indicating that ChlR1 is essential for placental formation. Detailed analysis of cells isolated from Ddx11-/- embryos revealed a G2/M cell cycle delay, an increased frequency of chromosome missegregation, decreased chromosome cohesion, and increased aneuploidy. To examine whether ChlR proteins are required for arm cohesion and for loading of the cohesin complex, further studies were preformed in ChlR1 siRNA treated cells. These studies revealed that ChlR1 is required for proper sister chromatid arm cohesion and that cohesin complexes bind more loosely to chromatin in the absence of ChlR1. Taken together, these studies provide the first data indicating that the ChlR1 helicase is essential for proper binding of the cohesin complex to both the centromere and the chromosome arms, and indicate that ChlR1 is essential for embryonic development and the prevention of aneuploidy in mammals.

Open Access Article

Bin1 Homolog Hob1 Supports a Rad6-Set1 Pathway of Transcriptional Repression in Fission Yeast

Arivudainambi Ramalingam and George C. Prendergast
Pages 1655 - 1662
http://dx.doi.org/10.4161/cc.6.13.4413
Abstract | PDF

Bin1 encodes a mammalian BAR adapter protein with a nuclear anti-oncogenic function that is poorly understood. To gain functional insights, we investigated the role of the fission yeast homolog hob1+ in growth arrest and survival of cells treated with phleomycin, a DNA damaging drug. Unlike wild-type cells, hob1∆ cells treated with phleomycin displayed a defective growth arrest phenotype, elongating abnormally without septation or cytokinesis and eventually losing viability. Genetic investigations suggested that the survival defect in hob1∆ cells reflected a deficiency in a Rad6 pathway involving histone methyltransferase Set1 that leads to transcriptional repression. In support of this connection, transcription of telomeric and centromeric heterochromatin that is normally silenced by a Rad6/Set1-dependent mechanism was aberrantly activated in hob1∆ cells. Taken together, these findings suggest that hob1+ may support a mechanism of transcriptional repression possibly relevant to the role of Bin1 in cancer suppression.




LETTERS TO THE EDITOR

Open Access Article

The Tumor Suppressor RASSF1A Does not Interact with Cdc20, an Activator of the Anaphase-Promoting Complex

Limin Liu, Katrin Baier, Reinhard H. Dammann and Gerd P. Pfeifer
Pages 1663 - 1665
http://dx.doi.org/10.4161/cc.6.13.4435
Abstract | PDF

Not yet available.

Open Access Article

Bacterial DUF199/COG1481 Proteins Including Sporulation Regulator WhiA are Distant Homologs of LAGLIDADG Homing Endonucleases that Retained Only DNA Binding

Lukasz Knizewski and Krzysztof Ginalski
Pages 1666 - 1670
http://dx.doi.org/10.4161/cc.6.13.4471
Abstract | PDF

Not yet available.