Table of Contents

Volume 8, Issue 21

  November 1, 2009

  Pages 3433 - 3609

View covers archive

 Issue Catalogue (MARC XML)

EDITORIAL

Open Access Article

pRB/CKI pathways at the interface of cell cycle and development

Victor Ambros
Pages 3433 - 3434
http://dx.doi.org/10.4161/cc.8.21.10102
Abstract | PDF

Comment on: The cyclin-dependent kinase inhibitors, cki-1 and cki-2, act in overlapping but distinct pathways to control cell-cycle quiescence during C. elegans development. Buck SH, et al. Cell Cycle 2009; 8:2613-20.




EDITORIALS: CELL CYCLE FEATURES

Open Access Article

SKAnking with Ska3: Essential role of Ska3 in cell division revealed by combined phenotypic profiling

Mirko Theis, Maciej Paszkowski-Rogacz and Frank Buchholz
Pages 3435 - 3437
http://dx.doi.org/10.4161/cc.8.21.9813
Abstract | PDF

Comment on: Theis M, et al. EMBO J 2009; 28:1453-65.

Open Access Article

A possible crosstalk between DNA repair pathways and angiogenesis

Triantafyllos Chavakis, Valeria V. Orlova and Harald F. Langer
Pages 3438 - 3439
http://dx.doi.org/10.4161/cc.8.21.9750
Abstract | PDF

Comment on: Economopoulou M, et al. Nat Med 2009; 15:553-58.

Open Access Article

Spindle assembly checkpoint, aneuploidy and tumorigenesis

Min Li and Pumin Zhang
Page 3440
http://dx.doi.org/10.4161/cc.8.21.9688
Abstract | PDF

Comment on: Li M, et al. J Cell Biol 2009; 185:983-94.

Open Access Article

Caspase-8 as a potential mediator of pro-tumorigenic signals

Darren Finlay, Amy Howes and Kristina Vuori
Pages 3441 - 3442
http://dx.doi.org/10.4161/cc.8.21.9649
Abstract | PDF

Comment on: Finlay D, et al. Cancer Res 2007; 67:11704-11.

Open Access Article

Guarding the guardian: Mdmx plays important roles in setting p53 basal activity and determining biological responses in vivo

Yunyuan V. Wang, Mark Wade and Geoffrey M. Wahl
Pages 3443 - 3444
http://dx.doi.org/10.4161/cc.8.21.9744
Abstract | PDF

Comment on: Wang YV, et al. Cancer Cell 2009; 16:33-43.

Open Access Article

BRCA2: Shining light on the regulation of DNA-binding selectivity by RAD51

Aura Carreira and Stephen C. Kowalczykowski
Pages 3445 - 3447
http://dx.doi.org/10.4161/cc.8.21.9748
Abstract | PDF

Comment on: Carreira A, et al. Cell 2009; 136:1032-43.

Open Access Article

The Pso4 complex splices into the DNA damage response

Randy J. Legerski
Pages 3448 - 3449
http://dx.doi.org/10.4161/cc.8.21.9760
Abstract | PDF

Comment on: Zhang N, et al. J Biol Chem 2005; 280:40559-67.

Open Access Article

Turning on the β-cell identity in the pancreas

Patrick Collombat and Ahmed Mansouri
Pages 3450 - 3451
http://dx.doi.org/10.4161/cc.8.21.9791
Abstract | PDF

Comment on: Collombat P, et al. Cell 2009;138:449-62..




CELL CYCLE NEWS & VIEWS

Open Access Article

An unusual case of self-defense

Andreas Vogt and John S. Lazo
Pages 3452 - 3454
http://dx.doi.org/10.4161/cc.8.21.10148
Abstract | PDF

Comment on: Involvement of MKP-1 and Bcl-2 in acquired cisplatin resistance in ovarian cancer cells. Wang J, et al. Cell Cycle 2009; 8:3191–8.

Open Access Article

Induction of apoptosis by viruses: What role does the nucleolus play?

Mark O.J. Olson
Pages 3452 - 3454
http://dx.doi.org/10.4161/cc.8.21.10162
Abstract | PDF

Comment on: Alphavirus M1 induces apoptosis of malignant glioma cells via downregulation and nucleolar translocation of p21WAF1/CIP1 protein. Hu J, et al. Cell Cycle 2009; 8:3328–39.

Open Access Article

Spindle function in yeast: A human motor to the rescue

Honglei Liu and Sharyn A. Endow
Pages 3452 - 3454
http://dx.doi.org/10.4161/cc.8.21.10163
Abstract | PDF

Comment on: Distinct Kinesin-14 mitotic mechanisms in spindle bipolarity. Simeonov DR, et al. Cell Cycle 2009; 8:In press.




EXTRA VIEWS

Open Access Article

p27 as Jekyll and Hyde: Regulation of cell cycle and cell motility

Michelle D. Larrea, Seth A. Wander and Joyce Slingerland
Pages 3455 - 3461
http://dx.doi.org/10.4161/cc.8.21.9789
Abstract | PDF

p27 is a key regulator of cell proliferation. While it opposes cell cycle progression by binding to and inhibiting cyclin E-Cdk2, T157/198 phosphorylation of p27 promotes its assembly of D-type cyclin-CDKs. In addition to its actions on the cell cycle, p27 regulates CDK-independent cytoplasmic functions. In human cancers, oncogenic activation of the PI3K signaling pathway often results in cytoplasmic mislocalization of p27. Cytoplasmic p27 plays an important role in cell motility and migration; it binds and modulates activation of the RhoA/ROCK cascade. p27:RhoA binding is facilitated by p27 phosphorylation at threonine 198. Accumulation of cytoplasmic p27 leads to increased cellular motility, a critical event in tumor metastasis. Further characterization of post-translational modifications governing p27 localization and its action on RhoA and the actin cytoskeleton may provide critical insights into human cancer metastasis.

Open Access Article

MicroRNA responses and stress granule formation modulate the DNA damage response

Joris Pothof, Nicole S. Verkaik, Jan H.J. Hoeijmakers and Dik C. van Gent
Pages 3462 - 3468
http://dx.doi.org/10.4161/cc.8.21.9835
Abstract | PDF

DNA damage induced by UV irradiation provokes profound changes in gene expression. Both transcriptional regulation and posttranslational modification of proteins have been known for many years, but the involvement of microRNAs in regulation of mRNA translation has been described only recently. This level of gene expression regulation appears to operate at the intermediate time points between fast protein modifications (within minutes) and much slower transcriptional reprogramming (which takes several hours to days to develop). MicroRNAs most clearly contribute to regulation of cell cycle checkpoints and apoptosis, but may also influence other aspects of cellular metabolism, differentiation and proliferation. Interestingly, the RNA silencing machinery redistributes into cytoplasmic RNA granules, termed stress granules (SGs), in cells that go through mitosis after UV irradiation. We discuss the implications of these findings for our understanding of the DNA damage response.

Open Access Article

MicroRNA-145 in vascular smooth muscle cell biology: A new therapeutic target for vascular disease

Chunxiang Zhang
Pages 3469 - 3473
http://dx.doi.org/10.4161/cc.8.21.9837
Abstract | PDF

Vascular smooth muscle cell (VSMC) phenotypic modulation and proliferation are critical cellular events in the development of a variety of proliferative vascular diseases. However, the molecular mechanisms involved in cellular events are still unclear. MicroRNAs (miRNAs) represent a novel class of small, non-coding RNAs that negatively regulate gene expression via degradation or translational inhibition of their target mRNAs. In a previous study, we identified that miR-145 is the most abundant miRNA in normal arteries and VSMCs. However, the roles of miR-145 in VSMC biology and vascular disease are unknown. In our recent Circulation Research article, we found that the expression of miR-145 is significantly downregulated in dedifferentiated VSMCs and in balloon-injured arteries. Moreover, both in vitro and in vivo studies demonstrated that miR-145 is a critical modulator of VSMC phenotype and proliferation. This review article summarizes the current research progress regarding the roles of miR-145 in VSMC biology and discusses the potential therapeutic opportunities surrounding this miRNA in vascular disease.

Open Access Article

Paradoxical roles of FAK in tumor cell migration and metastasis

Yanhua Zheng and Zhimin Lu
Pages 3474 - 3479
http://dx.doi.org/10.4161/cc.8.21.9846
Abstract | PDF

Focal adhesion kinase (FAK), as a key mediator of signaling induced by integrins, plays an instrumental role in many cellular functions, including cell survival and proliferation. Many studies have reported that FAK is a positive regulator of normal cell migration and cancer cell metastasis. However, emerging evidence shows that FAK—under certain oncogenic signaling, such as that initiated by activated Ras and some growth factor receptor kinases—negatively regulates cancer cell migration. Activated Ras may promote tumor cell migration by dephosphorylation of FAK at Y397 and facilitation of focal adhesion turnover at the leading edge of cells.

Open Access Article

Targeting oncogenic signaling pathways by exploiting nanotechnology

Sudipta Basu, Padmaparna Chaudhuri and Shiladitya Sengupta
Pages 3480 - 3487
http://dx.doi.org/10.4161/cc.8.21.9851
Abstract | PDF

Two scientific areas have recently emerged that can revolutionize cancer chemotherapy. First, an understanding of the different cellular signaling pathways implicated in the development and progression of cancer resulting in poor prognosis and drug resistance, have identified potential drug targets. Inhibitors of signal transduction pathways are currently in the clinics. Secondly, nanotechnology has emerged as an exciting multidisciplinary field promising to provide breakthrough solutions to the problems of optimizing the efficacy or therapeutic index of anticancer agents. The promise of nanotechnology lies in the ability to engineer customizable nanoscale constructs that can be loaded with one or more payloads such as chemotherapeutics, targeting units, imaging and diagnostic agents. This review addresses the potential integration of these two approaches to engineer nanoparticles that can target various signal transduction pathways in cancer.

Open Access Article

The Alox5 gene is a novel therapeutic target in cancer stem cells of chronic myeloid leukemia

Yaoyu Chen, Dongguang Li and Shaoguang Li
Pages 3488 - 3492
http://dx.doi.org/10.4161/cc.8.21.9852
Abstract | PDF

Cancer stem cells (CSCs) are believed to be the initiating cells for many types of blood cancer and some solid tumors, and curative therapies of these cancers require eradicating CSCs. Specific targeting of CSCs but not normal stem cell counterparts is a correct strategy for developing new anti-cancer therapies, and the success of this approach relies on identification of specific target genes in CSCs. Using BCR-ABL-induced chronic myeloid leukemia (CML) as a cancer model, we recently identified arachidonate 5-lipoxygenase (5-LO) gene (Alox5) as a critical regulator for leukemia stem cells (LSCs) in CML. Without Alox5, BCR-ABL fails to induce CML in mice due to the impairments of the functions of LSCs. The lack of Alox5 does not significantly affect the functions of normal hematopoietic stem cells. In addition, Zileuton, a specific 5-LO inhibitor, also causes the impairments of the functions of LSCs in a similar manner. Our results prove the principle that CSC-specific genes that play key roles in cancer development can be identified and inhibition of these genes can lead to eradication of these cells for cure. Here, we further discuss the mechanisms of Alox5 in CML, and the use of Zileuton as a potential and promising drug in eradicating LSCs in CML and other myeloproliferative diseases. We believe that our discovery of the role of Alox5 in regulating the function of LSCs in CML reminds us of viewing CSCs at a different angel. We predict that CSCs in other types of cancer also utilize specific regulatory pathways to control their survival and self-renewal, and inhibition of these pathways profoundly suppresses CSCs but not their normal stem cell counterparts. Specific targeting of CSCs without causing significant harm to normal stem cells should be a correct direction to go in developing novel therapeutic strategies in the future.




PERSPECTIVES

Open Access Article

Regulation of blood-testis barrier dynamics by focal adhesion kinase (FAK): An unexpected turn of events

C. Yan Cheng and Dolores D. Mruk
Pages 3493 - 3499
http://dx.doi.org/10.4161/cc.8.21.9833
Abstract | PDF

The blood-testis barrier (BTB) is conferred by co-existing tight junctions (TJs), basal ectoplasmic specialization (basal ES), desmosome-like junctions and gap junctions (GJs) between adjacent Sertoli cells near the basement membrane in the seminiferous epithelium.  While the concept of the BTB has been known for more than a century and its significance to spermatogenesis discerned for more than five decades, its regulation has remained largely unknown.  Recent studies, however, have demonstrated that focal adhesion kinase (FAK), a modulator of the integrin-based signaling that plays a crucial role on cell movement, apoptosis, cell survival and gene expression at the focal adhesion complex (FAC, also known as focal contact, a cell-matrix anchoring junction type), is an integrated component of the BTB, associated with the TJ-integral membrane protein occludin and its adaptor zonula occludens-1 (ZO-1).  Herein, we summarize recent findings in the field regarding the significance of FAK in conferring BTB integrity based on some unexpected observations.  We also critically discuss the role of FAK in regulating the timely "opening" and "closing" of the BTB to facilitate the transit of primary preleptotene spermatocytes across the BTB at stage VIII of the seminiferous epithelial cycle of spermatogenesis.  Lastly, we propose a working model, which can be used to design future functional experiments to explore the involvement of FAK in BTB dynamics by investigators in the field.

Open Access Article

The diverse roles of RNA helicases in RNAi

Aaron M. Ambrus and Maxim V. Frolov
Pages 3500 - 3505
http://dx.doi.org/10.4161/cc.8.21.9887
Abstract | PDF

RNA interference (RNAi) is a regulatory gene silencing system found in nearly all eukaryotic organisms that employs small RNAs, typically 20-25 nucleotides long, to target complementary sequences found in mRNAs. RNA helicases use ATP to unwind double-stranded RNA (dsRNA), and are known to participate at nearly every level of RNA metabolism. A multitude of RNA helicases have been isolated from screens for essential RNAi factors, and even the earliest models of the RNAi pathway have presumed an RNA helicase to function at the level of small RNA duplex unwinding. However, while many components that function in RNAi have been uncovered and characterized, the exact placement in the pathway and ascription of a specific biochemical function of an RNA helicase in RNAi remains elusive. Recent studies have delved deeper into the precise role of some RNA helicases. Surprisingly, these studies have revealed nontraditional roles, which may not even require the helicase activity. Such findings suggest that RNA helicases regulate gene silencing at nearly every level of the RNAi pathways.




REVIEWS

Open Access Article

MicroRNAs: Crucial multi-tasking components in the complex circuitry of tumor metastasis

Scott Valastyan and Robert A. Weinberg
Pages 3506 - 3512
http://dx.doi.org/10.4161/cc.8.21.9802
Abstract | PDF

Distant metastases are the underlying cause of patient mortality in an overwhelming majority of human carcinomas. Certain microRNAs have recently been found capable of regulating the process of tumor metastasis. In this review, we highlight recent advances within this rapidly emerging field, endeavor to connect known microRNA pathways with recent conceptual advances in the larger field of metastasis research, and speculate regarding the future utility of microRNAs in the diagnosis and treatment of human cancers. Assessed collectively, current evidence suggests that the pleiotropic activities of microRNAs endow them with the capacity to function as crucial, yet previously unappreciated, nodes within already-identified metastasis regulatory circuitry. This has important implications for our understanding of the pathogenesis of high-grade malignancies.

Open Access Article

MicroRNAs in early vertebrate development

Alessandro Rosa and Ali H. Brivanlou
Pages 3513 - 3520
http://dx.doi.org/10.4161/cc.8.21.9847
Abstract | PDF

During embryonic development, a precise and tightly regulated hierarchy of gene expression is necessary to ensure the proper formation of all cell types and organs.  In all animals and plants, microRNAs play a prominent role in the control of gene expression at the post-transcriptional level. In the last few years, microRNAs have emerged as important players during embryogenesis. As suggested by recent reports, microRNAs regulate crucial developmental processes, such as organizer induction, cell fate determination and body axis formation. In this review, we will discuss the role of microRNAs in early development of vertebrate model systems and in human embryonic stem cells, as an in vitro paradigm for human development.

Open Access Article

Mechanisms of epigenetic inheritance: Copying of Polycomb repressed chromatin

Nicole J. Francis
Pages 3521 - 3526
http://dx.doi.org/10.4161/cc.8.21.9876
Abstract | PDF

A key problem in gene regulation is how transcription patterns can be stably maintained in dividing cells. The formation and propagation of chromatin structures is believed to underlie stable gene expression patterns, including those maintained by Polycomb Group proteins. Recent studies focused on how Polycomb Group proteins and the chromatin structures they create behave during DNA replication and have begun to shed light onto mechanisms by which chromatin structures may be propagated through S-phase.  These studies suggest that both segregation of chromatin features to newly replicated chromatin and a feedback loop consisting of histone modification and recognition of this modification may contribute to inheritance. Results are discussed in light of other links between Polycomb proteins and DNA replication, and other systems in which maintenance of repression is believed to involve propagation of heritable chromatin structures.

Open Access Article

Bioelectric controls of cell proliferation: Ion channels, membrane voltage and the cell cycle

Douglas J. Blackiston, Kelly A. McLaughlin and Michael Levin
Pages 3527 - 3536
http://dx.doi.org/10.4161/cc.8.21.9888
Abstract | PDF

All cells possess long-term, steady-state voltage gradients across the plasma membrane. These transmembrane potentials arise from the combined activity of numerous ion channels, pumps, and gap junction complexes. Increasing data from molecular physiology now reveal that the role of changes in membrane voltage controls, and is in turn controlled by, progression through the cell cycle. We review recent functional data on the regulation of mitosis by bioelectric signals, and the function of membrane voltage and specific potassium, sodium, and chloride ion channels in the proliferation of embryonic, somatic, and neoplastic cells. Its unique properties place this powerful, well-conserved, but still poorly-understood signaling system at the center of the coordinated cellular interactions required for complex pattern formation. Moreover, disregulation of ion channel expression and function is increasingly observed to be not only a useful marker but likely a functional element in oncogenesis. New advances in genomics and the development of in vivo biophysical techniques suggest exciting opportunities for molecular medicine, bioengineering, and regenerative approaches to human health.




REPORTS

Open Access Article

Cdh1 controls the stability of TACC3

Jen-Chong Jeng, Ying-Mei Lin, Chiou-Hong Lin and Hsiu-Ming Shih
Pages 3537 - 3544
http://dx.doi.org/10.4161/cc.8.21.9935
Abstract | PDF

Transforming acidic coiled-coil protein 3 (TACC3) was reported to be important for regulating mitotic spindle assembly and chromosome segregation. While the protein level of TACC3 was shown to be altered during cell cycle progression, the molecular mechanism in controlling TACC3 level is unclear. Here, we show that TACC3 protein level can be regulated by Cdh1, a well known activator of anaphase-promoting complex/cyclosome. We identified Cdh1 as an interacting partner of TACC3 by a yeast array screen. Both in vitro and in vivo binding studies indicated that TACC3 can form complexes with Cdh1. Depletion of endogenous Cdh1 prolonged TACC3 protein level during mitotic exit. Alteration of Cdh1 level by ectopic overexpression or siRNA knockdown correlated well with an increase or decrease of ubiquitinated TACC3, respectively. Furthermore, the domain mapping studies of TACC3 revealed that multiple domains are involved in Cdh1-regulated degradation of TACC3. Altogether, our findings suggest that Cdh1 controls TACC3 protein stability during mitotic exit.

Open Access Article

Downregulation of ΔNp63α in keratinocytes by p14ARF-mediated SUMO-conjugation and degradation

Maria Vivo, Antonella Di Costanzo, Paola Fortugno, Alessandra Pollice, Viola Calabrò and Girolama La Mantia
Pages 3545 - 3551
http://dx.doi.org/10.4161/cc.8.21.9954
Abstract | PDF

The tumor suppressor p14ARF inhibits cell growth in response to oncogenic stress in a p53¬dependent and independent manner. However, new physiologic roles for ARF activation have been proposed. We have previously demonstrated that ARF interacts with p63, influencing its transcriptional activity. p63 is a member of the p53 family involved in skin and limb development, as well as in the homeostasis of mature epidermis. Here, we show that, in human keratinocytes, as well as in tumor-derived cell lines, ARF targets ΔNp63α, the most abundantly expressed p63 isoform, to proteasomal degradation by stimulating its sumoylation. Interestingly, we have observed an increase of ARF expression in differentiating keratinocytes, that is concomitant to the already described upregulation of SUMO2/3. Remarkably, we found that ΔNp63α is preferentially sumoylated by SUMO2, instead of SUMO1, and p14ARF increases the efficiency of this process.

Open Access Article

Identification and characterization of CAC1 as a novel CDK2-associated cullin

Ying Kong, Nan Kejun and Yuxin Yin
Pages 3552 - 3561
http://dx.doi.org/10.4161/cc.8.21.9955
Abstract | PDF

Cell cycle progression is tightly controlled by cyclins and cyclin-dependent kinases (CDKs). CDK2 plays a crucial role in regulating cell cycle progression, but how CDK2 is regulated is still incompletely understood. In this study, we report the identification and characterization of a novel gene CAC1 that regulates CDK2 activity. The open reading frame sequence of this gene encodes a protein of 369 amino acids which contains a Cullin domain, and this protein is physically associated with CDK2. As such, we have designated it Cdk-Associated Cullin1, or CAC1. CAC1 is highly expressed in cancer tissues and cancer cell lines. Interestingly, CAC1 is expressed in a cell cycle-dependent manner and its expression is high in late G1 to S phase. Knockdown of CAC1 by RNAi inhibits cell proliferation and induces G1/S arrest. Since CAC1 interacts with CDK2 and promotes the kinase activity of CDK2 protein, we propose that CAC1 is a novel cell cycle associated protein capable of promoting cell proliferation. Our data provide insight into the mechanism by which CDK2 is regulated and the molecular basis of cell cycle progression in cancer.

Open Access Article

Modification of survival pathway gene expression in human breast cancer cells by tetraiodothyroacetic acid (tetrac)

Anna B. Glinskii, Gennadi V. Glinsky, Hung-Yun Lin, Heng-Yuan Tang, Mingzeng Sun, Faith B. Davis, Mary K. Luidens, Shaker A. Mousa, Aleck H. Hercbergs and Paul J. Davis
Pages 3562 - 3570
http://dx.doi.org/10.4161/cc.8.21.9963
Abstract | PDF

Tetraiodothyroacetic acid (tetrac) inhibits the cellular actions of thyroid hormone initiated at the hormone receptor on plasma membrane integrin αvβ3.  Via interaction with the integrin, tetrac is also capable of inhibiting the angiogenic effects of vascular endothelial growth factor and basic fibroblast growth factor.  MDA-MB-231 cells are estrogen receptor-negative human breast cancer cells shown to be responsive to tetrac in terms of decreased cell proliferation.  Here we describe actions initiated at the cell surface receptor by unmodified tetrac and nanoparticulate tetrac on a panel of survival pathway genes in estrogen receptor-negative human breast cancer (MDA-MB-231) cells.  Nanoparticulate tetrac is excluded from the cell interior.  Expression of apoptosis inhibitors XIAP (X-linked inhibitor of apoptosis) and MCL1 (myeloid cell leukemia sequence 1) was downregulated by nanoparticulate tetrac in these breast cancer cells whereas apoptosis-promoting CASP2 and BCL2L14 were upregulated by the nanoparticulate formulation.  Unmodified tetrac affected only XIAP expression.  Expression of the angiogenesis inhibitor thrombospondin 1 (THBS1) gene was increased by both formulations of tetrac, as was the expression of CBY1, a nuclear inhibitor of catenin activity.  The majority of differentially regulated Ras-oncogene family members were downregulated by nanoparticulate tetrac. The latter downregulated expression of epidermal growth factor receptor gene and unmodified tetrac did not.  Nanoparticulate tetrac has coherent anti-cancer actions on expression of differentially-regulated genes important to survival of MDA-MB-231 cells.

Open Access Article

Distinct Kinesin-14 mitotic mechanisms in spindle bipolarity

Dimitre R. Simeonov, Katelyn Kenny, Lan Seo, Amanda Moyer, Jessica Allen and Janet L. Paluh
Pages 3571 - 3583
http://dx.doi.org/10.4161/cc.8.21.9970
Abstract | PDF

Kinesin-like proteins are integral to formation and function of a conserved mitotic spindle apparatus that directs chromosome segregation and precedes cell division. Ubiquitous to the mechanism of spindle assembly and stability are balanced Kinesin-5 promoting and Kinesin-14 opposing forces. Distinct Kinesin-14 roles in bipolarity in eukaryotes have not been shown, but are suggested by γ-tubulin-based pole interactions that affect establishment and by microtubule cross-linking and sliding that maintain bipolarity and spindle length. Distinct roles also imply specialized functional domains. By cross-species analysis of compatible mechanisms in establishing mitotic bipolarity we demonstrate that Kinesin-14 human HSET (HsHSET) functionally replaces Schizosaccharomyces pombe Pkl1 and its action is similarly blocked by mutation in a Kinesin-14 binding site on γ-tubulin. Drosophila DmNcd localizes preferentially to bundled interpolar microtubules in fission yeast and does not replace SpPkl1. Analysis of twenty-six Kinesin-14 derivatives, including Tail, Stalk or Neck-Motor chimeras, for spindle localization, spindle assembly and mitotic progression defined critical domains. The Tail of SpPkl1 contains functional elements enabling its role in spindle assembly that are distinct from but transferable to DmNcd, whereas HsHSET function utilizes both Tail and Stalk features. Our analysis is the first to demonstrate distinct mechanisms between SpPkl1 and DmNcd, and reveal that HsHSET shares functional overlap in spindle pole mechanisms.

Open Access Article

p53-dependent inhibition of TrxR1 contributes to the tumor-specific induction of apoptosis by RITA

Elisabeth Hedström, Sofi Eriksson, Joanna Zawacka-Pankau, Elias S.J. Arnér and Galina Selivanova
Pages 3584 - 3591
http://dx.doi.org/10.4161/cc.8.21.9977
Abstract | PDF

Thioredoxin reductase 1 (TrxR1) is a key regulator in many redox-dependent cellular pathways, and is often overexpressed in cancer. Several studies have identified TrxR1 as a potentially important target for anticancer therapy. The low molecular weight compound RITA (NSC 652287) binds p53 and induces p53-dependent apoptosis. Here we found that RITA also targets TrxR1 by non-covalent binding, followed by inhibition of its activity in vitro and by inhibition of TrxR activity in cancer cells. Interestingly, a novel ~130 kDa form of TrxR1, presumably representing a stable covalently linked dimer, and an increased generation of reactive oxygen species (ROS) were induced by RITA in cancer cells in a p53-dependent manner. Similarly, the gold-based TrxR inhibitor auranofin induced apoptosis related to oxidative stress, but independently of p53 and without apparent induction of the ~130 kDa form of TrxR1. In contrast to the effects observed in cancer cells, RITA had no impact on TrxR or ROS formation in normal fibroblasts (NHDF). The inhibition of TrxR1 can sensitize tumor cells to agents that induce oxidative stress and may directly trigger cell death. Thus, our results suggest that a unique p53-dependent effect of RITA on TrxR1 in cancer cells might synergize with p53-dependent induction of pro-apoptotic genes and oxidative stress, thereby leading to a robust induction of cancer cell death, without affecting non-transformed cells.

Open Access Article

3’UTR mediated regulation of the cyclin D1 proto-oncogene

Anagha Deshpande, Alessandro Pastore, Aniruddha. J. Deshpande, Yvonne Zimmermann, Grit Hutter, Marc Weinkauf, Christian Buske, Wolfgang Hiddemann and Martin Dreyling
Pages 3592 - 3600
http://dx.doi.org/10.4161/cc.8.21.9993
Abstract | PDF

In mantle cell lymphoma (MCL), over-expression of cyclin D1 is the hallmark of malignant transformation and results from it’s juxtaposition to the immunoglobulin heavy chain enhancer. In addition, genomic deletions or point mutations leading to premature truncation of the cyclin D1 3’UTR have been reported in a several MCL patients  as well as in cell lines isolated from various tumors types. We demonstrate that the expression of cyclin D1 with or without the 3’UTR has different phenotypic consequences in stably transduced fibroblasts, with the hyper-proliferative phenotype of cyclin D1 closely linked to the deletion of its 3’UTR. In our study, the loss of the cyclin D1 3’UTR led to a significant upregulation of the protein. However, the loss of AU-rich elements (AREs) from the cyclin D1 UTR results in a significant decrease in cyclin D1 protein and UTR-tagged reporter expression. In contrast, the levels of cyclin D1 protein can be significantly reduced by microRNAs of the miR15/16 family and the miR17-92 cluster that directly target the cyclin D1 3’UTR. Most importantly, these microRNAs regulated the levels of the endogenous cyclin D1 protein encoded by an mRNA with a full 3’UTR but not with 3’ UTR deletions. Taken together, our data highlight the regulatory role of the cyclin D1 3’UTR in the expression and phenotype of cyclin D1 and suggest that in MCL and solid tumors with cyclin D1 3’UTR mutations, the loss of microRNA target sites, rather than ARE elements contribute to the pathogenic over-expression of the cyclin D1 protein.

Open Access Article

Foxp3-expressing T regulatory cells and mast cells in acute graft-versus-host disease of the skin

Karen N. Wu, Robert V.B. Emmons, Michael P. Lisanti, John L. Farber and Agnieszka K. Witkiewicz
Pages 3601 - 3605
http://dx.doi.org/10.4161/cc.8.21.9999
Abstract | PDF

Acute graft-versus-host disease (aGVHD) limits the effectiveness of allogeneic hematopoietic stem cell transplantation. Foxp3 is required for the development and function of CD4+/CD25+ regulatory T cells (T-regs). Foxp3-expressing T-regs are thought to protect against GVHD. Mast cells are thought to be essential in CD4+/CD25+ regulatory T cell-dependent peripheral tolerance. Twenty biopsies of skin with grades I-III aGVHD were stained for Foxp3 and CD117. Inflammation was quantified by a 4 point scale, 0=no inflammation, 1=<25% of 20x field, 2=25-50%, and 3=>50%. T-regs and mast cells were quantified by a 4 point scale, 0=no cells per 20x field, 1=<5 cells per 20x field, 2=5-10 cells, and 3=>10 cells. T-regs were positively correlated with both inflammation and aGVHD grade. Twelve cases with low T-regs had mild inflammation and lower grades of aGVHD and 6 cases with high T-regs had dense inflammatory infiltrate and higher grades of aGVHD. The number of T-regs, mast cells and density of the inflammatory infiltrate were positively correlated only in cases with mild inflammation. In aGVHD of the skin, T-regs increased with the degree of inflammation and GVHD grade. Mast cells were present at the same density whether aGVHD was of lower or higher grade.




LETTERS TO THE EDITOR

Open Access Article

PKR is not a universal target of tumor suppressor p53 in response to genotoxic stress

Mashrur Rahman, Christopher Lem, Hala Muaddi and Antonis Koromilas
Pages 3606 - 3607
http://dx.doi.org/10.4161/cc.8.21.9848
PDF

Open Access Article

Aurora B kinase, an immobile passenger!

Marlène Delacour-Larose, Hong-Lien Vu and Annie Molla
Pages 3608 - 3609
http://dx.doi.org/10.4161/cc.8.21.9939
PDF