Table of Contents

Volume 10, Issue 5

  March 1, 2011

  Pages 723 - 852

View covers archive

 Issue Catalogue (MARC XML)

EDITORIALS: CELL CYCLE FEATURES

Open Access Article

Slowly cycling versus rapidly cycling intestinal stem cells: Distinct roles or redundancy

Diana L. Carlone and David T. Breault
Pages 723 - 724
http://dx.doi.org/10.4161/cc.10.5.14867
Abstract | PDF

Comment on: Montgomery RK, et al. Proc Natl Acad Sci USA 2011; 108:179-84.

Open Access Article

Messengers made for micro-destruction

Michael W. Gordon and Yong Li
Pages 725 - 726
http://dx.doi.org/10.4161/cc.10.5.14865
Abstract | PDF

Comment on: Guo et al, Nature 2010; 466:835-40.

Open Access Article

Role for histone deacetylase 3 in maintenance of genome stability

Srividya Bhaskara and Scott W. Hiebert
Pages 727 - 728
http://dx.doi.org/10.4161/cc.10.5.14866
Abstract | PDF

Comment on: Bhaskara S, et al. Cancer Cell 2010; 18:436-47.

Open Access Article

The PKA paradox: Is Bim the answer?

Andrew M. Coley, Diane Moujalled and Hamsa Puthalakath
Pages 729 - 730
http://dx.doi.org/10.4161/cc.10.5.14869
Abstract | PDF

Comment on: Moujalled D, et al. EMBO Rep 2011; 12:77-83.

Open Access Article

Plugging PKA into ERK scaffolds

F. Donelson Smith, Lorene K. Langeberg and John D. Scott
Pages 731 - 732
http://dx.doi.org/10.4161/cc.10.5.14902
Abstract | PDF

Cancers often arise in part through derangements in protein kinase signaling. A striking example of this is the finding that approximately 30% of human tumors have mutations in Ras or B-Raf, leading to aberrant ERK kinase activation. Kinase signaling networks are often organized by scaffolding and anchoring proteins that help shape the dynamics of signal processing. AKAP-Lbc associates with the ERK scaffold protein KSR-1 to organize a growth factor and cAMP responsive signaling network. AKAP-Lbc also directs PKA phosphorylation of KSR-1 on a critical residue to ensure maximal signaling efficiency.

Open Access Article

Cell cycle control by a methylation-phosphorylation switch

Simon M. Carr and Nicholas B. La Thangue
Pages 733 - 734
http://dx.doi.org/10.4161/cc.10.5.14958
Abstract | PDF

Comment on: Carr SM, et al. EMBO J. 2011; 30:317-27.




CELL CYCLE NEWS & VIEWS

Open Access Article

KAPping PML nuclear body number

Paolo Salomoni
Pages 735 - 740
http://dx.doi.org/10.4161/cc.10.5.14927
Abstract | PDF

Comment on: Kepkay R, et al. Cell Cycle 2011; 10:308-322.

Open Access Article

Unleash the wild type: Restoration of p53 suppressive activity in skin cancer

Shalom Madar, Perry Stambolsky and Varda Rotter

http://dx.doi.org/10.4161/cc.10.5.14928
Abstract | PDF

Comment on: Bao MC, et al. Cell Cycle 2011; 10:301-307.

Open Access Article

Linking oncogenes to invasion in thyroid cancer

Matthew D. Ringel

http://dx.doi.org/10.4161/cc.10.5.14929
Abstract | PDF

Comment on: Nowicki TS, et al. Cell Cycle 2011; 10:100-107.

Open Access Article

SAHF, to senesce or not to senesce?

Maciej K. Kocylowski and Thanos D. Halazonetis

http://dx.doi.org/10.4161/cc.10.5.14975
Abstract | PDF

Comment on: Kosar M, et al. Cell Cycle 2011; 10:457-68.

Open Access Article

A Janus molecule provides a rational reshape to a multi-functional drug

Julio Padron

http://dx.doi.org/10.4161/cc.10.5.14977
Abstract | PDF

Comment on: Donia M, et al. Cell Cycle 2011; 10:492-9.




MEETING REPORT

Open Access Article

Cell biology and medicine at the crossroads

Zahid H. Shah
Pages 741 - 744
http://dx.doi.org/10.4161/cc.10.5.14918
Abstract | PDF

Report on the meeting: Frontiers in Cell Biology and Medicine, University of York, UK, 26-29 September 2010




EXTRA VIEWS

Open Access Article

The flip side of the coin: Role of ZRF1 and histone H2A ubiquitination in transcriptional activation

Holger Richly and Luciano Di Croce
Pages 745 - 750
http://dx.doi.org/10.4161/cc.10.5.14795
Abstract | PDF

We have recently reported that the protein ZRF1 specifically binds to monoubiquitinated histone H2A and derepresses Polycomb target genes at the onset of cellular differentiation. Our results suggest that ZRF1 exerts its function in a two-step mechanism, by initially displacing the Polycomb-repressive complex 1 (PRC1) from chromatin and subsequently acting together with histone H2A-specific deubiquitinases to facilitate transcriptional activation of its target genes. These findings demonstrate an ambiguity of the epigenetic monoubiquitin mark at histone H2A. Once considered to be a hallmark of gene silencing, it is now clear that this mark can also be utilized as a recruitment platform for proteins engaged in gene activation. Genome-wide analyses demonstrate that ZRF1 is recruited to typical Polycomb target genes, thereby putting it in a position to have an impact on differentiation and animal development. This molecular mechanism for ZRF1 may represent one of the first steps in switching silenced genes to a transcriptionally active state. We discuss here our recent findings in the light of progress made in understanding Polycomb-mediated silencing.

Open Access Article

Paradoxical microRNAs: Individual gene repressors, global translation enhancers

Subramanya Srikantan, Bernard S. Marasa, Kevin G. Becker, Myriam Gorospe and Kotb Abdelmohsen
Pages 751 - 759
http://dx.doi.org/10.4161/cc.10.5.14825
Abstract | PDF

In mammalian cells, microRNAs regulate the expression of target mRNAs generally by reducing their stability and/or translation, and thereby control diverse cellular processes such as senescence. We recently reported the differential abundance of microRNAs in young (early-passage, proliferating) relative to senescent (late-passage, non-proliferating) WI-38 human diploid fibroblasts. Here we report that the levels of the vast majority of mRNAs were unaltered in senescent compared to young WI-38 cells, while overall mRNA translation was potently reduced in senescent cells. Downregulation of Dicer or Drosha, two major enzymes in microRNA biogenesis, lowered microRNA levels, but, unexpectedly, it also reduced global translation. While a reduction in Dicer levels markedly enhanced cellular senescence, reduction of Drosha levels did not, suggesting that the Drosha/Dicer effects on translation may be independent of senescence, and further suggesting that microRNAs may directly or indirectly enhance mRNA translation in WI-38 cells. We discuss possible scenarios through which Dicer/Drosha/microRNAs could enhance translation.

Open Access Article

The transcription factor FOXM1c binds to and transactivates the promoter of the tumor suppressor gene E-cadherin

Inken Wierstra
Pages 760 - 766
http://dx.doi.org/10.4161/cc.10.5.14827
Abstract | PDF

This study demonstrates for the first time that FOXM1c transactivates the murine E-cadherin promoter. It shows also that the purified DNA-binding domain of FOXM1c binds to the murine and human E-cadherin promoters in vitro, namely to a perfectly conserved FOXM1 site. Thus, this study identifies E-cadherin as a new direct FOXM1c target gene. This finding is surprising because E-cadherin is a tumor suppressor gene whereas FOXM1 is a proliferation-associated and tumorigenesis-promoting transcription factor. The transmembrane glycoprotein E-cadherin mediates cell-cell adhesion in adherens junctions. Its expression is frequently lost or reduced in human tumors, which correlates with poor prognosis. Downregulation of E-cadherin represents a central event in epithelial-to-mesenchymal transition. In contrast, FOXM1 contributes to oncogenic transformation and participates in tumor initiation and progression. It is overexpressed in many human cancers and a high FOXM1 level correlates with poor prognosis. FOXM1 stimulates cell proliferation and promotes cell cycle progression at the G1/S- and G2/M-transitions. The surprising finding that FOXM1c transactivates the promoter of the tumor suppressor gene E-cadherin points to a tumor-suppressive property of FOXM1. This view is supported by FOXM1's new tumor suppressor role as others reported that urethane-induced lung tumorigenesis is increased in mice with an endothelial cell-specific foxm1 deletion.

Open Access Article

Kelch repeat proteins control yeast PKA activity in response to nutrient availability

Roli Budhwar, Guoqiang Fang and Jeanne P. Hirsch
Pages 767 - 770
http://dx.doi.org/10.4161/cc.10.5.14828
Abstract | PDF

Regulation of protein kinase A (PKA) by binding of cAMP to the regulatory subunit and the resulting release of the active catalytic subunit is a very well established mechanism of kinase activation. We have shown recently that PKA in budding yeast is also subject to an additional level of regulation that that modulates its activity in response to nutrient availability. Nutrient regulation of PKA activity requires a pair of proteins, Gpb1 and Gpb2, that contain several kelch repeats, a sequence motif that predicts that they fold into a β-propeller structure. The regulatory process mediated by Gpb1 and Gpb2 causes an increase in the stability and phosphorylation of the PKA regulatory subunit Bcy1 in response to low extracellular glucose concentrations. Phosphorylation of serine-145 of Bcy1 controls its stability, and other phosphorylation events at the cluster of serines at positions 74-84 correlate with changes in nutrient availability. Here we present data consistent with a model in which the effects of Gpb1 and Gpb2 on Bcy1 are an indirect consequence of their primary effects on the PKA catalytic subunits.

Open Access Article

Understanding PLZF: Two transcriptional targets, REDD1 and smooth muscle α-actin, define new questions in growth control, senescence, self-renewal and tumor suppression

Marina Kolesnichenko and Peter K. Vogt
Pages 771 - 775
http://dx.doi.org/10.4161/cc.10.5.14829
Abstract | PDF

PLZF can function as a transcriptional activator or as a transcriptional repressor. Recent studies have identified two direct transcriptional targets of PLZF, REDD1 and smooth muscle α-actin. REDD1 is activated by PLZF. It mediates the PLZF-dependent downregulation of TORC1 and is responsible for the maintenance of pluripotency in cultures of spermatogonial progenitor cells. This activity may extend to other stem-like cell types. The effect of REDD1 on TORC1 also raises the possibility that REDD1 controls cell growth, tumorigenicity and senescence. The regulatory loop extending from PLZF via REDD1 to TORC1 identifies REDD1 as a critical determinant of TOR activity. The transcription of smooth muscle α-actin is repressed by PLZF. In fibroblasts, this downregulation is accompanied by a change of cell shape and a dramatic reorganization of the cytoskeleton. It is also correlated with the acquisition of cellular resistance to oncogenic transformation. The resistance is selective, it works against some oncoproteins but not against others. The molecular mechanisms underlying the changes in the cytoskeleton and in the susceptibility to oncogenic transformation are unknown. However these changes are dependent on the activity of RAS and thus probably involve the RAC/RHO family of proteins.




REPORTS

Open Access Article

Filamin A stimulates cdc25C function and promotes entry into mitosis

Elphine Telles, Mansa Gurjar, Ketaki Ganti, Dipika Gupta and Sorab N. Dalal
Pages 776 - 782
http://dx.doi.org/10.4161/cc.10.5.14954
Abstract | PDF

The activity of the dual specificity phosphatase cdc25C is required for mitotic progression though the mechanisms by which cdc25C is activated prior to mitosis in human cells remain unclear. The data presented herein show that the actin binding protein Filamin A forms a complex with cdc25C in vivo and binds preferentially to the mitotic form of cdc25C. Co-expression of Filamin A with cdc25C results in an increase in PCC induced by cdc25C, while knocking down Filamin A expression reduces the levels of PCC induced by cdc25C overexpression. Further, only a Filamin A fragment that forms a complex with both cdc25C and cyclin B1 and retains the dimerization domain can stimulate the ability of cdc25C to induce PCC. These results suggest that Filamin A provides a platform for the assembly of the cyclin B1-cdk1- cdc25C complex resulting in cdk1 activation and mitotic progression.

Open Access Article

Mip1 associates with both the Mps1 kinase and actin, and is required for cell cortex stability and anaphase spindle positioning

Christopher P. Mattison, Jason Stumpff, Linda Wordeman and Mark Winey
Pages 783 - 793
http://dx.doi.org/10.4161/cc.10.5.14955
Abstract | PDF

The Mps1 family of protein kinases contributes to cell cycle control by regulating multiple microtubule cytoskeleton activities. We have uncovered a new Mps1 substrate that provides a novel link between Mps1 and the actin cytoskeleton. We have identified a conserved human Mps1 (hMps1) interacting protein we have termed Mps1 interacting protein-1 (Mip1). Mip1 defines an uncharacterized family of conserved proteins that contain coiled-coil and calponin homology domains. We demonstrate that Mip1 is a phosphoprotein that interacts with hMps1 in vitro and in vivo and is a hMps1 substrate. Mip1 exhibits dynamic localization during the cell cycle; Mip1 localizes to the actin cytoskeleton during interphase, the spindle in early mitosis, and the cleavage furrow during cytokinesis. Mip1 function is required to ensure proper spindle positioning at the onset of anaphase after cells begin furrow ingression. Cells depleted of Mip1 exhibit aberrant mitotic actin filament organization, excessive membrane blebbing, dramatic spindle rocking, and chromosome distribution errors during early cytokinesis producing high numbers of binucleate cells. Our data indicate that Mip1 is a newly recognized component of the actin cytoskeleton that interacts with hMps1 and that it is essential to ensure proper segregation of the genome during cell cleavage.

Open Access Article

Stat1 is a suppressor of ErbB2/Neu-mediated cellular transformation and mouse mammary gland tumor formation

Jennifer F. Raven, Virginie Williams, Shuo Wang, Michel L. Tremblay, William J. Muller, Joan E. Durbin and Antonis E. Koromilas
Pages 794 - 804
http://dx.doi.org/10.4161/cc.10.5.14956
Abstract | PDF

The anti-tumor function of Stat1 as a regulator of innate immunity and tumor immune surveillance has been long studied and is well understood; however, less clear is its tumor-site specific role. Although Stat1 phosphorylated at tyrosine (Y) 701 and serine (S) 727 is essential for interferon (IFN) signalling, its function in signalling induced in breast cancer cells is not understood. Herein, we show that Stat1 Y701 phosphorylation is increased in human breast tumor cells with elevated levels of ErbB2/HER-2 and in cells transfected with ErbB2/Neu. However, pharmacological inhibition of ErbB2/HER-2 results in the inhibition of Stat1 Y701 phosphorylation indicating an atypical role of phosphorylated Stat1 in the inhibition of ErbB2/HER-2 signalling. Consistent with this notion, we found that Stat1 suppresses tumor development by an activated form of ErbB2/Neu in mouse embryonic fibroblasts in xenograft tumor assays; however, this anti-tumor function of Stat1 does not rely on Y701 and S727 phosphorylation. Experiments with transgenic mice demonstrated that Stat1 acts to suppress Neu-mediated breast tumorigenesis through immune regulatory and tumor-site specific mechanisms. Our data reveal a previous uncharacterized anti-tumor activity of Stat1 in ErbB2/Neu-mediated cell transformation and breast oncogenesis with possible implications in the diagnosis and treatment of ErbB2-positive breast cancers.

Open Access Article

Drosophila melanogaster Cyclin G coordinates cell growth and cell proliferation

Floria Faradji, Sébastien Bloyer, Delphine Dardalhon-Cuménal, Neel B. Randsholt and Frederique Peronnet
Pages 805 - 818
http://dx.doi.org/10.4161/cc.10.5.14959
Abstract | PDF

Mammalian Cyclins G1 and G2 are unconventional cyclins whose role in regulating the cell cycle is ambiguous. Cyclin G1 promotes G2/M cell cycle arrest in response to DNA damage whereas ectopic expression of CCNG2, that encodes Cyclin G2, induces G1/S cell cycle arrest. The only Drosophila Cyclin G was previously shown to be a transcriptional regulator that interacts with the chromatin factor Corto and controls expression of the homeotic gene Abdominal B. It is very close to mammalian Cyclin G1 and G2 except in its N-terminal region, that interacts with Corto, and that seems to have been acquired in dipterans. Ubiquitous misregulation of Cyclin G (CycG) using transgenic lines lengthens development and induces phenotypes suggesting growth or proliferation defects. Using tissue-specific misregulation of CycG and FACS, we show that overproduction of Cyclin G produces small cells whereas shortage produces large cells, suggesting that Cyclin G negatively regulates cell growth. Furthermore, overexpression of CycG lengthens the cell cycle, with a prominent effect on G1 and S phases. Genetic interactions with Cyclin E suggest that Cyclin G prevents G1 to S transition and delays S phase progression. Control of cell growth and cell cycle by Cyclin G might be achieved via interaction with a network of partners, notably the cyclin-dependent kinases CDK4 and CDK2.

Open Access Article

Three independent mechanisms for arrest in G₂ after ionizing radiation

Kirsti Solberg Landsverk, Sebastian Patzke, Idun Dale Rein, Caroline Stokke, Heidi Lyng, Paula M. De Angelis and Trond Stokke
Pages 819 - 829
http://dx.doi.org/10.4161/cc.10.5.14968
Abstract | PDF

Cell cycle checkpoints ensure that eukaryotic cells do not enter mitosis after ionizing irradiation (IR). The G₂-arrest after IR is the result of activation of multiple signalling pathways, the contributions of which vary with time after irradiation. We have studied the time evolution of the IR-induced G₂-arrest in human B-lymphocyte cancer cell lines, as well as the molecular mechanisms responsible for the arrest. Cells that were in G₂ phase at the time of irradiation experienced a transient arrest that blocked entry into mitosis at 0-2hours after IR (0.5 or 4Gy). Activation of ATM and CHEK2 occurred at the same time as this early arrest and was, like the arrest, abrogated by the ATM-inhibitor KU-55933. A late, permanent and ATM-independent arrest (≥6hours after IR) of cells that were in G₂/S/G₁ at the time of irradiation (4Gy) was inactivated by caffeine. This late G₂-arrest could not be explained by down-regulation of genes with functions in G₂/mitosis (e.g. PLK1, CCNB1/2), since the down-regulation was transient and not accompanied by reduced protein levels. However, the persistent phosphorylation of CHEK1 after 4Gy suggested a role for CHEK1 in the late arrest, consistent with the abrogation of the arrest in CHEK1–depleted cells. TP53 was not necessary for the late G₂-arrest, but mediated an intermediate arrest (2-10hours after IR) independently of ATM and CHEK1. In conclusion, the IR-induced arrest in G₂ is mediated by ATM immediately after irradiation, with TP53 for independent and transient back-up, while CHEK1 is necessary for the late arrest.

Open Access Article

The bulge area is the major hair follicle source of nestin-expressing pluripotent stem cells which can repair the spinal cord compared to the dermal papilla

Fang Liu, Aisada Uchugonova, Hiroaki Kimura, Chuansen Zhang, Ming Zhao, Lei Zhang, Karsten Koenig, Jennifer Duong, Ryoichi Aki, Norimitsu Saito, Sumiyuki Mii, Yasuyuki Amoh, Kensei Katsuoka and Robert M. Hoffman
Pages 830 - 839
http://dx.doi.org/10.4161/cc.10.5.14969
Abstract | PDF

Nestin has been shown to be expressed in the hair follicle, both in the bulge area (BA) as well as the dermal papilla (DP). Nestin-expressing stem cells of both the BA and DP have been previously shown to be pluripotent and be able to form neurons and other non-follicle cell types. The nestin-expressing pluripotent stem cells from the DP have been termed skin precursor or SKP cells. The objective of the present study was to determine the major source of nestin-expressing pluripotent stem cells in the hair follicle and to compare the ability of the nestin-expressing pluripotent stem cells from the BA and DP to repair spinal cord injury. Transgenic mice in which the nestin promoter drives GFP (ND-GFP) were used in order to observe nestin expression in the BA and DP. Nestin-expressing DP cells were found in early and middle anagen. The BA had nestin expression throughout the hair cycle and to a greater extent than the DP. The cells from both regions had very long processes extending from them as shown by two-photon confocal microscopy. Nestin-expressing stem cells from both areas differentiated into neuronal cells at high frequency in vitro. Both nestin-expressing DP and BA cells differentiated into neuronal and glial cells after transplantation to the injured spinal cord and enhanced injury repair and locomotor recovery within four weeks. Nestin-expressing pluripotent stem cells from both the BA and DP have potential for spinal cord regeneration, with the BA being the greater and more constant source.

Open Access Article

Ionizing radiation-induced TAp63α phosphorylation at C-terminal S/TQ motifs requires the N-terminal transactivation (TA) domain

Dal-Ah Kim, Byong-Linne Lee and Eun-Kyung Suh
Pages 840 - 849
http://dx.doi.org/10.4161/cc.10.5.15008
Abstract | PDF

TAp63α, a homolog of p53 and one of six alternatively spliced p63 isoforms, is a critical mediator of the ionizing radiation (IR)-induced DNA damage response in female germ cells and also tumor suppression in somatic cells. The ΔNp63α isoform, lacking the N-terminal transactivation (TA) domain, is associated with oncogenic potential. The mechanism of p63 functional regulation is not well understood. TAp63α is phosphorylated by ionizing radiation (IR)-induced DNA damage and gene transactivation is likely to be involved. Based on information gleaned from studies on p53, we explored the possibility that TAp63α S/TQ sites may be phosphorylated by IR-induced DNA damage. Our findings show a wortmanin-sensitive kinase phosphorylates TAp63α at C-terminal Ser-Gln and Thr-Gln (S/TQ) sites but not N-terminal S/TQ sites. ΔNp63α, lacking the TA domain, and TAp63γ, lacking C-terminal domains, including S/TQ sites, fail to undergo IR-induced phosphorylation. We propose a model for TA domain-dependent C-terminal phosphorylation drawing from previously described self-inactivating intramolecular interaction between N-terminal TA domain and C-terminal Transactivation Inhibitory Domain (TID) of TAp63α. A specific topology adopted only by TAp63α, but not possible for ΔNp63α or TAp63γ, may lead to TAp63α-specific kinase recruitment, phosphorylation and self-inactivation release. TID-lacking TAp63γ, like p53, is constitutively active and thus may forgo phosphorylation-dependent activation. Thus, p53 is regulated by protein stabilization and TAp63α by protein activation but both appear to involve S/TQ phosphorylation. The difference in phosphorylation potential of TAp63α and ΔNp63α may in part help explain why the two similar isoforms have diametrically opposite tumor suppression and oncogene functions, respectively.




LETTER TO THE EDITOR

Open Access Article

BAG3 protein is induced during cardiomyoblast differentiation and modulates myogenin expression

Margot De Marco, Maria Caterina Turco and Alessandra Rosati
Pages 850 - 852
http://dx.doi.org/10.4161/cc.10.5.14964
PDF