Table of Contents

Volume 5, Issue 9

  May 1, 2006

  Pages 907 - 1010

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 Issue Catalogue (MARC XML)

EXTRA VIEWS

Open Access Article

Cell Cycling through Cdc25A: Transducer of Cytokine Proliferative Signals

C. Kittipatarin, WQ. Li, D. Bulavin, S.K. Durum and A.R. Khaled
Pages 907 - 912
http://dx.doi.org/10.4161/cc.5.9.2693
Abstract | PDF

A balance between survival and proliferative signals maintains a constant number of T lymphocytes that populate the mammalian immune system, a process termed “homeostasis”. Central to this process is the availability of a stromal cell product – the cytokine interleukin-7 (IL-7). We recently showed that IL-7, in addition to protecting cells from apoptosis, drives the cell cycling of lymphocytes through regulation of the stability of the phosphatase, Cdc25A, a key activator of cyclin-dependent kinases (cdks). IL-7 achieves this by controlling the activity of p38 MAP kinase (MAPK), which can phosphorylate Cdc25A, triggering its degradation. Sustained expression of Cdc25A had diverse effects: it promoted cell cycling, even in presence of cell cycle inhibitors such p27Kip1, and prevented cell shrinkage in response to cytokine deprivation. Herein we show a role for Cdc25A as a transducer of cytokine-driven proliferation and discuss novel implications for cell growth from the perspective of the requirements for maintenance of lymphocyte homeostasis.

Open Access Article

Recombination Activating Genes (RAG) in Lymphoma Development

Brian B. Haines, Chun Jeih Ryu and Jianzhu Chen
Pages 913 - 916
http://dx.doi.org/10.4161/cc.5.9.2732
Abstract | PDF

The recombination activating genes (RAG) play a central role in the generation of a diverse immune repertoire by mediating DNA recombination events at antigen receptor loci in developing B and T lymphocytes. However, inappropriate RAG activity throughout the genome has been implicated in a large variety of human and mouse lymphomas. Mechanisms by which RAG can provoke or perpetuate lymphoma include deregulation of certain genes by translocation to antigen receptor regulatory regions, the formation of chimeric oncogenes, inactivation of tumor suppressor or micro-RNA loci, or activation of oncogenes. Here we present the T cell receptor enhancer (Eb) deficient mouse as a tractable in vivo model system to study the role of RAG activity in the context of lymphoma development, and contrast our system with those of others. We posit a general hypothesis that virtually any mutation that impairs early lymphocyte development at stages when RAG is expressed can constitute a pro-carcinogenic event. Our model system provides a means to assess the roles of RAG activity in human lymphoid malignancies.

Open Access Article

Genesis and Wanderings: Origins and Migrations in Asymmetrically Replicating Mitochondrial DNA

Timothy A. Brown and David A. Clayton
Pages 917 - 921
http://dx.doi.org/10.4161/cc.5.9.2710
Abstract | PDF

Mammalian mitochondria maintain a small circular genome that encodes RNA and polypeptides that are essential for the generation of ATP through oxidative phosphorylation. The mechanism of replication of mammalian mitochondrial DNA (mtDNA) has recently been a topic of controversy. New evidence has led to a modified strand-displacement model that reconciles much of the current data. This revision stems from a new appreciation for alternative light-strand origins. We consider here some of the potential mechanisms for light-strand origin initiation. We also consider further the susceptibility of branch migration within replicating mtDNA molecules. The existence of alternative lightstrand origins and a propensity for branch migration in replicating mtDNA molecules exposes a new array of possible configurations of mtDNA. The assortment and assignment of these forms is relevant to the interpretation of experimental data and may also yield insight into the molecular basis of replication errors.

Open Access Article

Control of Uterine Cell Proliferation and Differentiation by C/EBPb: Functional Implications for Establishment of Early Pregnancy

Milan K. Bagchi, Srinivasa R. Mantena, Athilakshmi Kannan and Indrani C. Bagchi
Pages 922 - 925
http://dx.doi.org/10.4161/cc.5.9.2712
Abstract | PDF

Implantation of the embryo to the uterine wall is regulated by the concerted actions of maternal steroid hormones, progesterone (P) and estrogen (E). During early pregnancy, the stromal cells surrounding the implanted embryo proliferate and then undergo differentiation to form the "decidual" tissue, which protects and nurtures the embryo. The CCAAT enhancer-binding protein beta (C/EBPb), a transcription factor, has recently been identified as a novel mediator of the actions of E and P during decidualization. Female mice lacking C/EBPb gene are infertile and their uteri displayed a complete lack of response to a deciduogenic stimulus, indicating a critical role of this transcription factor in regulating the decidualization program. Initial studies indicate impairments in proliferation and differentiation of stromal cells in C/EBPb null uteri. C/EBPb is also essential for E-induced proliferation of uterine epithelial cells in non-pregnant mice. It is postulated that C/EBPb controls the expression of critical molecules that regulate proliferation and function of epithelial and stromal cells in the female reproductive tract during the establishment of early pregnancy.

Open Access Article

ATF3 Regulates the Stability of p53: A Link to Cancer

Chunhong Yan and Douglas D. Boyd
Pages 926 - 929
http://dx.doi.org/10.4161/cc.5.9.2714
Abstract | PDF

ATF3 is a member of the ATF/CREB family of transcription factors involved in the cellular response to a large variety of stresses including DNA damage. However, neither the signaling leading to nor the biological significance of its induction upon stress is well understood. Although it is generally believed that ATF3 exerts its function in the stress response by regulating transcription, to date, only a limited number of target genes have been identified. We recently reported that ATF3 interacts with the tumor suppressor p53 to increase its stability in the genotoxic response. While providing the cell a general means of responding to diverse adverse environment cues, this mechanism confers ATF3 with an ability to promote tumor suppressor functions. Conversely, dysfunction of ATF3 impairs the p53-mediated cellular response to DNA damage, allowing cells to be readily transformed by oncogenes. Consistent with this notion is the observation of down-regulated ATF3 expression in most human cancers. Therefore, our findings indicate that ATF3 intersects with p53-associated pathways ensuring genomic integrity. The ability of ATF3 to stabilize p53-induced pathways thus represents a means of effectively countering DNA damage caused by environmental insult the latter leading to oncogene activation and ultimately malignant transformation.




PERSPECTIVES

Open Access Article

E2F1 and Telomerase: Alliance in the Dark Side

Marta M. Alonso, Juan Fueyo-Margareto, W.K. Alfred Yung and Candelaria Gomez-Manzano
Pages 930 - 935
http://dx.doi.org/10.4161/cc.5.9.2698
Abstract | PDF

Cancer arises from a stepwise accumulation of genetic changes. Among these changes, deregulation of the Rb/E2F1 pathway and constitutively active telomerase are pivotal milestones for the attainment of immortality and maintaining the neoplastic phenotype. We recently showed the Rb/E2F1 pathway to be a direct modulator of telomerase activity in normal and cancer cells, specifically in malignant gliomas. In addition, we reported that the correlation between the levels of expression of E2F1 and hTERT -the catalytic subunit of telomerase- in a subset of patients with glioblastoma multiforme confers clinical relevance to the role of E2F1 in triggering or maintaining hTERT expression. Here we review the evidence supporting the mechanistic linkage between E2F1 and telomerase activation. We also consider the clinical implications of this association in terms of prognostic significance and opportunities for the development of new and more rational therapeutic strategies.

Open Access Article

p63 and p73: Life and Death in Squamous Cell Carcinoma

James W. Rocco and Leif W. Ellisen
Pages 936 - 940
http://dx.doi.org/10.4161/cc.5.9.2716
Abstract | PDF

The p53 family member p63 plays an essential role in the developing epithelium, and overexpression of the ΔNp63a isoform is frequently observed in human squamous cell carcinomas (SCCs). These findings have suggested that ΔNp63a might function as an oncogene within squamous epithelial cells. Nevertheless, the mechanism by which ΔNp63a might promote tumorigenesis remains poorly understood, and data from mouse models implies that the p63 locus might in fact function as a tumor suppressor in these same tissues. A recent study using RNA interference in human SCC-derived cell lines shows that ΔNp63a mediates an essential survival function in human SCC cells by virtue of its ability to suppress the pro-apoptotic function of the related p53 family member p73. These findings support an oncogenic role for ΔNp63a and they demonstrate the existence of critical physical and functional interactions between endogenous p53 family members in human cancer. Specific chemotherapeutic agents and future targeted approaches may be able to exploit this pathway to therapeutic advantage.

Open Access Article

Oxygen Sensing: Recent Insights from Idiopathic Erythrocytosis

Frank S. Lee, Melanie J. Percy and Mary Frances McMulli
Pages 941 - 945
http://dx.doi.org/10.4161/cc.5.9.2723
Abstract | PDF

Idiopathic erythrocytosis (IE) is a rare condition in which there is an increase in red cell mass and hematocrit. As it is typically driven by elevated or inappropriately normal erythropoietin (Epo) levels, it has the potential to reveal the identities of proteins involved in the oxygen sensing pathway that regulates the transcription factor, Hypoxia Inducible Factor (HIF), and hence Epo production in humans. One example of this is provided by Chuvash polycythemia, a form of erythrocytosis due to a mutation in the von Hippel Lindau tumor suppressor protein (VHL), a component of an E3 ubiquitin ligase complex that targets hydroxylated HIF for degradation. A recent report of familial erythrocytosis now implicates a different protein, Prolyl Hydroxylase Domain protein 2 (PHD2), which is an enzyme that hydroxylates HIF.

Open Access Article

PI 3-Kinases: Hidden Potentials Revealed

Peter K. Vogt, Andreas G. Bader and Sohye Kang
Pages 946 - 949
http://dx.doi.org/10.4161/cc.5.9.2725
Abstract | PDF

The potential oncogenicity of PI3-kinases is revealed by two principal mechanisms: mutations causing gain of function and over-expression of wild-type proteins. Cancer-specific mutations in PIK3CA, the gene coding for the catalytic subunit p110a of PI 3-kinase, are oncogenic in the animal. These mutations are therefore significant determinants of the oncogenic cellular phenotype in human tumors and are appropriate and promising targets for small molecule inhibitors. Over-expression of wild-type p110b, g, and d induces oncogenic transformation in cell culture. Although these non-alpha isoforms of PI 3-kinase have not been found mutated in human cancer, deregulated expression could contribute to cellular oncogenic properties and deserves increased attention.

Open Access Article

Connecting Temporal Identity to Mitosis: The Regulation of Hunchback in Drosophila Neuroblast Lineages

Joachim Urban and Ulrike Mettler
Pages 950 - 952
http://dx.doi.org/10.4161/cc.5.9.2727
Abstract | PDF

Both in vertebrates and invertebrates, neural stem cells generate different cell types at different times during development. It has been suggested that this process depends on temporal identity transitions of neural progenitors, but the underlying mechanism has not been resolved, yet. Recently, Drosophila neuroblasts (NBs) have been shown to be an excellent model system to investigate this subject. Here, changes in temporal identity are regulated by sequential and transient expression of transcription factors in the NB, such as Hunchback (Hb) and Krüppel (Kr). The temporal expression profile is maintained in the progeny. Hb is expressed first and thus defines the earliest identity in a given lineage. Transition to Kr requires the termination of hb expression which occurs in response to mitosis, and is mediated by Seven-up (Svp). Recent results provided evidence that the dependency of Svp activity on mitosis could be due to an inhibition of the nuclear export of svp mRNA. Furthermore, the maintenance of hb expression in the GMC is regulated by the activity of Prospero (Pros), a transcription factor which asymmetrically segregates into the GMC during mitosis and inhibits Svp activity on both, the transcriptional and posttranscriptional level. These results give first insights as to how temporal cell fate specification can be correlated with mitosis.

Open Access Article

Stop and Go: Anti-Proliferative and Mitogenic Functions of the Transcription Factor C/EBPβ

Thomas Sebastian and Peter F. Johnson
Pages 953 - 957
http://dx.doi.org/10.4161/cc.5.9.2733
Abstract | PDF

Oncogene-induced senescence (OIS) is an irreversible form of cell cycle arrest that can be elicited by over-expression of oncogenes such as RasV12 and requires activation of the Arf-p53 and RB tumor suppressor pathways. Increasing evidence implicates senescence as a bona fide tumor suppression mechanism in vivo. We recently discovered that the bZIP transcription factor C/EBPβ, a downstream target of Ras signaling, is an essential component of RasV12-mediated senescence in mouse embryo fibroblasts (MEFs). C/EBPβ induces cell cycle arrest through a mechanism requiring RB:E2F repressor complexes and negatively regulates several E2F target genes. Although C/EBPβ has tumor suppressor-like activity in MEFs, other observations point to critical pro-oncogenic functions for C/EBPβ in certain cancers. Here we review the evidence for positive and negative cell cycle regulation by C/EBPβ and discuss possible mechanisms by which this transcription factor could participate in both cellular senescence and oncogenic transformation.

Open Access Article

Evidence for Extrinsic Exonucleolytic Proofreading

Stephanie A. Nick McElhinny, Youri I. Pavlov and Thomas A. Kunkel
Pages 958 - 962
http://dx.doi.org/10.4161/cc.5.9.2736
Abstract | PDF

Exonucleolytic proofreading of DNA synthesis errors is one of the major determinants of genome stability. However, many DNA transactions that contribute to genome stability require synthesis by polymerases that naturally lack intrinsic 3´ exonuclease activity and some of which are highly inaccurate. Here we discuss evidence that errors made by these polymerases may be edited by a separate 3´ exonuclease, and we consider how such extrinsic proofreading may differ from proofreading by exonucleases that are intrinsic to replicative DNA polymerases.




REVIEW

Open Access Article

The Basal Phenotype of BRCA1-Related Breast Cancer: Past, Present and Future

Marc D Tischkowitz and William D. Foulkes
Pages 963 - 967
http://dx.doi.org/10.4161/cc.5.9.2713
Abstract | PDF

Many BRCA1-related tumors have a distinct histological characteristics which together have been called “basal-like”. Typically such tumors are ER-, HER2- and express cytokeratin 5/6, cytokeratin 8/18, EGFR and vimentin. These characteristics can be used to predict which breast cancers are most likely to be associated with germline BRCA1 mutations which has important implications for breast pathologists. Moreover, BRCA1-related breast cancers generally have a poorer prognosis which may paradoxically be more pronounced in node negative cancers. This may relate in part to a different pattern of metastatic spread with in increased frequency of brain and lung metastases in BRCA1 carriers. Conversely, BRCA1-related tumors may respond better to neoadjuvant chemotherapy and their characteristic molecular signature may provide opportunities to develop specific molecular targeted therapies akin to traztuzumab in HER2+ cancers. Finally, many of the phenotypic features of BRCA1-related tumors might also be found in putative breast stem cells and therefore characterization of the BRCA1 breast cancer phenotype will improve our understanding of sporadic breast carcinogenesis.




BRIEF REPORT

Open Access Article

Absence of BRAF Gene Mutation in Non-Melanoma Skin Tumors

Massimo Libra, Grazia Malaponte, Valentina Bevelacqua, Roberta Siciliano, Paola Castrogiovanni, Alberto Fulvi, Giuseppe Micali, Giovanni Ligresti, Maria C. Mazzarino, Franca Stivala, Salvatore Travali and James A. McCubrey
Pages 968 - 970
http://dx.doi.org/10.4161/cc.5.9.2724
Abstract | PDF

Basal cell carcinoma (BCC) is the most common skin cancer, and its incidence is increasing. It was proposed that the RAS oncogene significantly contributes to skin cancer development. Numerous BRAF mutations have been detected in melanoma biopsy specimens and cell lines. For the first time, in the present study, tumor biopsy specimens from 78 patients with BCC were screened for BRAF mutation within exons 11 and 15. Our results indicate that the BRAF gene does not appear to be frequently mutated in non-melanoma skin tumors such as BCC. These data suggest that other gene alterations may cause tumor development.




ANALYTICAL REPORT

Open Access Article

Prolonged Mitosis Versus Tetraploid Checkpoint: How p53 Measures the Duration of Mitosis

Mikhail V. Blagosklonny
Pages 971 - 975
http://dx.doi.org/10.4161/cc.5.9.2711
Abstract | PDF

Degradation of p53 requires transcription, and therefore inhibitors of transcription cause p53 accumulation. When transcription resumes, the p53 that accumulated in turn induces p21. During mitosis, chromosomes are condensed, the nuclear envelope is dissolved and transcription is absent. And, if a cell stays in mitosis too long, (e.g. mitotic arrest caused by Taxol or nocodazole), then p53 accumulates. This explains how p53 can measure mitotic time and perhaps represents the most fundamental function of p53.




REPORTS

Open Access Article

The DCX Superfamily 1: Common and Divergent Roles for Members of the Mouse DCX Superfamily

Frédéric M. Coquelle, Talia Levy, Sven Bergmann, Sharon Grayer Wolf, Daniela Bar-El, Tamar Sapir, Yehuda Brody, Irit Orr, Naama Barkai, Gregor Eichele and Orly Reiner
Pages 976 - 983
http://dx.doi.org/10.4161/cc.5.9.2715
Abstract | PDF

The doublecortin-like (DCX) domains serve as protein-interaction platforms. DCX tandem domains appear in the product of the X-linked doublecortin (DCX) gene, in retinitis pigmentosa –1 (RP1), as well as in other gene products. Mutations in the human DCX gene are associated with abnormal neuronal migration, epilepsy, and mental retardation; mutations in RP1 are associated with a form of inherited blindness, while DCDC2 has been associated with dyslectic reading disabilities. Motivated by the possible importance of this gene family, a thorough analysis to detect all family members in the mouse was conducted. The DCX-repeat gene superfamily is composed of eleven paralogs, and we cloned the DCX domains from nine different genes. Our study questioned which functions attributed to the DCX domain, are conserved among the different members. Our results suggest that the proteins with the DCX-domain have conserved and unique roles in microtubule regulation and signal transduction. All the tested proteins stimulated microtubule assembly in vitro. Proteins with tandem repeats stabilized the microtubule cytoskeleton in transfected cells, while those with single repeats localized to actin-rich subcellular structures, or the nucleus. All tested proteins interacted with components of the JNK/MAP-kinase pathway, while only a subset interacted with Neurabin 2, and a non-overlapping group demonstrated actin association. The sub-specialization of some members due to confined intracellular localization, and protein interactions may explain the success of this superfamily.

Open Access Article

Unmasking the Redundancy Between Cdk1 and Cdk2 at G2 Phase in Human Cancer Cell Lines

Lawrence L’Italien, Marcel Tanudji, Loren Russell and Xiao Min Schebye
Pages 984 - 993
http://dx.doi.org/10.4161/cc.5.9.2721
Abstract | PDF

A series of studies published in 2003 has challenged the essentiality of Cdk2. A recently published work indicates that cyclin E-Cdk1 compensates for Cdk2’s function at G1/S transition in Cdk2-/- Mefs. In this study, we uncovered a redundant mechanism between Cdk1 and Cdk2 at G2 in multiple cancer cell lines. When either Cdk2 or Cdk1 is ablated using RNAi, there were complex shifts of cyclin A towards its reciprocal partner, i.e., when Cdk2 is ablated, cyclin A redistributes to Cdk1; when Cdk1 is ablated, cyclin A forms more abundant complexes with Cdk2. Further, cyclin B redistributes to Cdk2 upon Cdk1 knockdown. These redistributions bring about increased kinase activities of corresponding complexes. Elimination of the compensatory mechanism by knockdown of both Cdk1 and Cdk2 using RNAi reveals phenotypes at G2 phase. The results suggest that the redistributed complexes contribute to the cyclin B-Cdk1 activation when either Cdk1 or Cdk2 alone is ablated and this redundancy masks Cdk2’s role when Cdk2 is singly ablated. It is also worth noting that the predominant G2 arrest described here, unlike those Cdk1-Cdk2 double ablated Mefs, raises a question of whether different Cdk activities are required for G1/S or G2/M progression in normal vs. cancer cells.

Open Access Article

ATR-Chk1 Axis Protects BCR/ABL Leukemia Cells from the Lethal Effect of DNA Double-Strand Breaks

Margaret Nieborowska-Skorska, Tomasz Stoklosa, Mandrita Datta, Agnieszka Czechowska, Lori Rink, Artur Slupianek, Mateusz Koptyra, Ilona Seferynska, Konrad Krszyna, Janusz Blasiak and Tomasz Skorski
Pages 994 - 1000
http://dx.doi.org/10.4161/cc.5.9.2722
Abstract | PDF

BCR/ABL-positive leukemia cells accumulated more replication-dependent DNA double-strand breaks (DSBs) than normal counterparts after treatment with cisplatin and MMC, as assessed by pulse field gel electrophoresis (PFGE) and neutral comet assay. In addition, leukemia cells could repair these lesions more efficiently than normal cells and eventually survive genotoxic treatment. Elevated levels of drug-induced DSBs in leukemia cells were associated with higher activity of ATR kinase, and enhanced phosphorylation of histone H2AX on serine 139 (γ-H2AX). γ-H2AX eventually started to disappear in BCR/ABL cells, while continued to increase in parental cells. In addition, the expression and ATR-mediated phosphorylation of Chk1 kinase on serine 345 were often more abundant in BCR/ABL-positive leukemia cells than normal counterparts after genotoxic treatment. Inhibition of ATR kinase by caffeine but not Chk1 kinase by indolocarbazole inhibitor, SB218078 sensitized BCR/ABL leukemia cells to MMC in a short-term survival assay. Nevertheless, both caffeine and SB218078 enhanced the genotoxic effect of MMC in a long-term clonogenic assay. This effect was associated with the abrogation of transient accumulation of leukemia cells in S and G2/M cell cycle phases after drug treatment. In conclusion, ATR - Chk1 axis was strongly activated in BCR/ABL-positive cells and contributed to the resistance to DNA cross-linking agents causing numerous replication-dependent DSBs.

Open Access Article

BRCA1 Downregulation Leads to Premature Inactivation of Spindle Checkpoint and Confers Paclitaxel Resistance

C. Chabalier, C. Lamare, C. Racca, M. Privat, A. Valette and F. Larminat
Pages 1001 - 1007
http://dx.doi.org/10.4161/cc.5.9.2726
Abstract | PDF

BRCA1 germline mutations predispose women to early onset, familial breast and ovarian cancer. BRCA1 has been recently implicated in the cellular response to agents that disrupt the mitotic spindle. In this report, we studied BRCA1 contribution to paclitaxel response in MCF-7 breast cancer cells. We show that MCF-7 cells transfected with BRCA1 siRNA display a significant increase in resistance to paclitaxel compared with the control cells. We next demonstrate that down-regulation of BRCA1 reduces the mitotic index and triggers premature cyclin B1 degradation and decrease in Cdk1 activity following paclitaxel treatment, suggesting that BRCA1 down-regulation results in precocious inactivation of the spindle checkpoint. These findings were confirmed by showing that BRCA1 down-regulation induces premature sister–chromatids separation in MCF-7 cells following spindle damage. Furthermore, we show that BRCA1 up-regulates the expression of the protein kinase BubR1, essential component of the functional spindle checkpoint, whose down-regulation is known to result in paclitaxel resistance in MCF-7 cells. Altogether, our findings support the notion that down-regulation of BRCA1 expression mediates paclitaxel resistance through premature inactivation of spindle checkpoint in MCF-7 breast cancer cells. They link BRCA1 to the mitotic checkpoint that plays an essential role in the maintenance of chromosomal stability.




LETTER TO THE EDITOR

Open Access Article

Non-Specific Detection of the Centrosomes by Antibodies Recognizing Phosphorylated ATM at Serine 1981

Keiji Suzuki, Mio Morimoto, Motohiro Yamauchi, Hiromi Yoshida, Seiji Kodama and Masami Watanabe
Pages 1008 - 1009
http://dx.doi.org/10.4161/cc.5.9.2720
Abstract | PDF

No abstract available.




REPLY

Open Access Article

Reply to Letter to the Editor

Elisa Oricchio, Chiara Saladino, Stefano Iacovelli, Silvia Soddu and Enrico Cundari
Page 1010
http://dx.doi.org/10.4161/cc.5.9.2774
Abstract | PDF

No abstract available.