Table of Contents

Volume 6, Issue 17

  September 1, 2007

  Pages 2087 - 2195

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EXTRA VIEWS

Open Access Article

Take Your "M" Time

Gustavo Baldassarre, Carlo M. Croce and Andrea Vecchione
Pages 2087 - 2090
http://dx.doi.org/10.4161/cc.6.17.4628
Abstract | PDF

Both entry and exit from Mitosis are driven through the fine modulation of Cdk1 activity by several proteins or protein complexes. It is well established that to entry into the M phase a cell requires Cdk1 to be fully activated in the nucleus by the CDC25A, B and C phosphatases. Then, at the onset of Anaphase Cdk1 activity suddenly drops mainly due to Cyclin B1 degradation, thus allowing exit from M phase. Recent data demonstrate that high Cdk1 activity is necessary also for proper chromosome segregation, since its premature drop determines acceleration of the progression from prophase to metaphase eventually with incorrect division of the DNA content. A primary role in maintaining high Cdk1 activity during prophase and metaphase is played by CDC25C phosphatase. During the M phase, the activity of CDC25C is regulated by the FEZ1/LZTS1 (LZTS1) tumor suppressor gene, which is able to prevent CDC25C degradation in mitotic cells. As a consequence, Lzts1 absence in mice results in accelerated mitotic progression, improper chromosome segregation and, eventually, in increased incidence of both spontaneous and carcinogen-induced cancer formation.

Open Access Article

COMMD1: A Novel Protein Involved in the Proteolysis of Proteins

Bart van de Sluis, Arjan J. Groot, Cisca Wijmenga, Marc Vooijs and Leo W. Klomp
Pages 2091 - 2098
http://dx.doi.org/10.4161/cc.6.17.4646
Abstract | PDF

COMMD1 is a protein which is associated with multiple cellular pathways, including NFκB signaling, copper homeostasis and sodium transport. Recently we found that COMMD1 is also essential for normal mouse embryogenesis. Embryos deficient for Commd1 are retarded and die between 9.5 and 10.5 dpc. Increased HIF-1 activity and elevated HIF-1α protein expression were observed in 9.5 dpc Commd1-deficient embryos. In line with these in vivo data, in vitro studies showed that reduced COMMD1 expression caused increased HIF-1α protein stability and HIF-1 activity. Functional characterization of COMMD1 in NFκB signaling and ATP7B-dependent biliary copper excretion suggested that COMMD1 also has a role in regulating the protein degradation of RelA (p65) and ATP7B. The exact function of COMMD1 in these pathways remains elusive but these recent studies suggest that COMMD1 is associated with the ubiquitin-proteasomal system for regulating protein stability.

Open Access Article

Bacterially-Derived Nanocells for Tumor-Targeted Delivery of Chemotherapeutics and Cell Cycle Inhibitors

Jennifer A. MacDiarmid, Jocelyn Madrid-Weiss, Nancy B. Amaro-Mugridge, Leo Phillips and Himanshu Brahmbhatt
Pages 2099 - 2105
http://dx.doi.org/10.4161/cc.6.17.4648
Abstract | PDF

Chemotherapeutic drug therapy in cancer is seriously hampered by severe toxicity primarily due to indiscriminate drug distribution and consequent collateral damage to normal cells. Molecularly targeted drugs such as cell cycle inhibitors are being developed to achieve a higher degree of tumor cell specificity and reduce toxic side effects. Unfortunately, relative to the cytotoxics, many of the molecularly targeted drugs are less potent and the target protein is expressed only at certain stages of the cell cycle thus necessitating regimens like continuous infusion therapy to arrest a significant number of tumor cells in a heterogeneous tumor mass. Here we discuss targeted drug delivery nanovectors and a recently reported bacterially-derived 400nm sized minicell that can be packaged with therapeutically significant concentrations of chemotherapeutic drugs, targeted to tumor cell surface receptors and effect intracellular drug delivery with highly significant anti-tumor effects in-vivo. We also report that molecularly targeted drugs can also be packaged in minicells and targeted to tumor cells with highly significant tumor growth-inhibition and regression in mouse xenografts despite administration of minute amounts of drug. This targeted intracellular drug delivery may overcome many of the hurdles associated with the delivery of cytotoxic and molecularly targeted drugs.

Open Access Article

Examples of Mathematical Modeling: Tales from the Crypt

Matthew D. Johnston, Carina M. Edwards, Walter F. Bodmer, Philip K. Maini and S. Jonathan Chapman
Pages 2106 - 2112
http://dx.doi.org/10.4161/cc.6.17.4649
Abstract | PDF

Mathematical modeling is being increasingly recognized within the biomedical sciences as an important tool that can aid the understanding of biological systems. The heavily regulated cell renewal cycle in the colonic crypt provides a good example of how modeling can be used to find out key features of the system kinetics, and help to explain both the breakdown of homeostasis and the initiation of tumorigenesis. We use the cell population model by Johnston et al. (2007) Proc. Natl. Acad. Sci. USA 104, 4008-4013, to illustrate the power of mathematical modeling by considering two key questions about the cell population dynamics in the colonic crypt. We ask: how can a model describe both homeostasis and unregulated growth in tumorigenesis; and to which parameters in the system is the model most sensitive? In order to address these questions, we discuss what type of modeling approach is most appropriate in the crypt. We use the model to argue why tumorigenesis is observed to occur in stages with long lag phases between periods of rapid growth, and we identify the key parameters.




PERSPECTIVES

Open Access Article

Chromatin Polymorphism and the Nucleosome Superfamily: A Genealogy

Christophe Lavelle and Ariel Prunell
Pages 2113 - 2119
http://dx.doi.org/10.4161/cc.6.17.4631
Abstract | PDF

Nucleosomes were discovered more than thirty years ago as the basic repeating units of chromatin. Since then, nucleosomes have progressively revealed their taste to come in many appearances, upon either adjunction of other proteins (e.g. a fifth histone or a non-histone protein, HMG-N), histone substitution for isoforms (histone variants), depletion of one or the two H2A-H2B dimers (sub-nucleosomes), intimate two-particle association, or isomeric structural alterations. The resulting entities, some of them are only transient, acquire new properties useful for their specific roles in chromatin function. These structures are presented here in the chronological order of their identification, from the chromatosome to the sub-nucleosomal hexasome and tetrasome, and from the dinucleosomal altosome and nucleodisome to the nucleosome variants and altered forms: the old lexosome and the most recent reversome.

Open Access Article

Role of β-Catenin in Adult Cardiac Remodeling

Laura Zelarayan, Christina Gehrke and Martin W. Bergmann
Pages 2120 - 2126
http://dx.doi.org/10.4161/cc.6.17.4632
Abstract | PDF

The adult heart has a uniform cellular response to adapt to injury after infarct or increased wall stress in chronic hypertension: hypertrophy of adult cardiomyocytes increases muscle fiber mass while at the same time apoptosis of cardiomyocytes may lead to further loss of contractile mass. The existence and quantitative amount of endogenous cardiac regeneration is currently under intense dispute, no clear picture has yet emerged. Recently, cardiac precursor cells and the signaling pathways controlling their differentiation in the adult organ have come into focus. In heart development, β-catenin was identified to play a biphasic role in cardiomyocyte differentiation. While initially WNT/β-catenin activation is required to commit mesenchymal cells to the cardiac lineage, downregulation of β-catenin is needed for cardiomyocyte differentiation at later stages. Recent genetic data published by our lab suggest β-catenin downregulation to be beneficial for adult cardiac remodeling. Here we discuss these data in the context of β-catenin´s role in adult cardiomyocyte hypertrophy, apoptosis and possibly regeneration.

Open Access Article

MicroRNAs and Cell Cycle Regulation

Michael Carleton, Michele A. Cleary and Peter S. Linsley
Pages 2127 - 2132
http://dx.doi.org/10.4161/cc.6.17.4641
Abstract | PDF

MicroRNAs (microRNAs) are abundant, ~21-25 nucleotide (nt) non-coding RNAs that mediate sequence-specific, post-transcriptional repression of mRNA targets. Consistent with observations that many microRNAs target transcripts encoding proteins directly or indirectly involved in cell cycle progression and cellular proliferation, alteration of microRNA levels can contribute to pathological conditions associated with loss of cell cycle control including tumorigenesis,. In this review we highlight recent data linking microRNAs to mammalian cell cycle regulation. We describe how specific miRNAs function within pathways that control cell cycle checkpoints. We discuss emerging evidence that support the idea that some microRNA activity may be cell cycle dependent, and we outline how the coordinate regulation of microRNA targets may influence cell cycle progression.

Open Access Article

hClp1, A Novel Kinase Revitalizes RNA Metabolism

Stefan Weitzer and Javier Martinez
Pages 2133 - 2137
http://dx.doi.org/10.4161/cc.6.17.4642
Abstract | PDF

The RNA-Induced Silencing Complex (RISC) is the effector complex in the RNA interference (RNAi) pathway. In order to become assembled into RISC, synthetic small interfering RNAs (siRNAs) are phosphorylated at the 5’ end upon transfection into cells. The enzymatic activity responsible for this phosphorylation event has so far remained elusive. Using a classical chromatographic approach, we recently identified and characterized hClp1 as the “siRNA-kinase” in HeLa cells. hClp1 is in fact a general RNA-kinase, and a component of the tRNA splicing endonuclease and the mRNA 3’ end formation machinery. We discuss the relevance of this finding, and provide further views and perspectives for the analysis of hClp1 in tRNA splicing, mRNA cleavage and polyadenylation and other RNA metabolic processes in which hClp1 might play a role.

Open Access Article

A Novel Role for Hedgehog in T-Cell Receptor Signaling: Implications for Development and Immunity

Nicola J. Rowbotham, Ariadne L. Hager-Theodorides, Anna L. Furmanski and Tessa Crompton
Pages 2138 - 2142
http://dx.doi.org/10.4161/cc.6.17.4644
Abstract | PDF

The Hedgehog (Hh) signaling pathway is a key regulator of both embryonic development and homeostasis of adult tissues, including thymus and blood. In the thymus, Hh signals for differentiation, survival and proliferation in the early stages of T cell development, before TCR gene rearrangement. Our recent data has shown that Hh signaling also modulates T cell receptor (TCR) signal strength in more mature T lineage cells. We showed that constitutive activation of the Hh pathway in thymocytes (by transgenic expression of the transcriptional activator form of Gli2) decreased TCR signal strength with profound consequences for the thymus - allowing self-reactive T cells to escape deletion and altering T cell CD4/CD8 lineage decisions. In contrast, in the Sonic Hh deficient thymus, TCR signaling was increased, again influencing both TCR repertoire selection and CD4/8 lineage commitment. In peripheral T cells, the transcriptional changes induced by activation of the Hh signaling pathway lead to reduced T cell activation. Hh signaling also attenuated ERK phosphorylation and proliferation in mature T cells on TCR ligation. Modulation of TCR signal strength by Hh pathway activation has importance for immunity as the presence or absence of Hh in the environment in which a T cell is activated would shape the immune response.

Open Access Article

Mdm2 Plays a Positive Role as an Effector of p53-Dependent Responses

Luciana E. Giono and James J. Manfredi
Pages 2143 - 2147
http://dx.doi.org/10.4161/cc.6.17.4647
Abstract | PDF

The p53 tumor suppressor is negatively regulated in cells by the Mdm2 protein. Mdm2 has therefore been the focus of intensive research aiming at using it as a target for cancer therapy with the ultimate goal of restoring p53 activity. Several studies have attempted to ablate Mdm2 expression or disrupt its interaction with p53 in cancer cells. While the p53-Mdm2 duo has concentrated a lot of attention, multiple new and diverse functions and targets of Mdm2 have been uncovered. Downregulation of Mdm2 using an siRNA approach has recently provided evidence for a new role of Mdm2 in the p53 response, by modulating the inhibition of the cyclin-dependent kinase 2 (cdk2) by p21. Here, this and other recent findings are discussed that support a new role for Mdm2 in the regulation of p53 response.

Open Access Article

Replicational Stress Selects for p53 Mutation

Andriy Marusyk and James DeGregori
Pages 2148 - 2151
http://dx.doi.org/10.4161/cc.6.17.4732
Abstract | PDF

p53 is a critical mediator of cellular responses to a variety of stresses. Given the frequency of p53 mutations in human malignancies and that disruption of p53 has been implicated in chemoresistance, understanding the factors that select for p53 disruption is important both for understanding tumor evolution and for designing cancer therapies. While it is widely believed that genotoxic stress selects for p53 mutations, the effects of DNA damaging agents on long-term proliferative potential are usually not affected by p53 status. Previous reports have demonstrated that despite being activated, p53 loss does not prevent cell cycle arrest and senescence in response to high levels of acute replicational stress. In contrast, we recently reported that chronic exposure of non-transformed cells to low, clinically relevant levels of replicational stress induces p53-dependent senescence-like arrest. Disruption of p53 or its target gene p21CIP1 antagonizes this arrest, leading to a long-term proliferative advantage. However, when replicational stress is associated with substantial DNA strand breaks, the ability of p53 disruption to up-regulate RAD51 dependent homologous recombination becomes important. Replicational stress is induced by many chemotherapeutic treatments and perhaps by some dietary deficiencies, and may be an important factor that selects for p53 mutations during cancer initiation and progression.




REVIEW

Open Access Article

The Tubulin Code

Kristen J. Verhey and Jacek Gaertig
Pages 2152 - 2160
http://dx.doi.org/10.4161/cc.6.17.4633
Abstract | PDF

Microtubules create diverse arrays with specific cellular functions such as the mitotic spindle, cilia, and bundles inside neurons. How microtubules are regulated to enable specific functions is not well understood. Recent work has shown that posttranslational modifications of the tubulin building blocks mark subpopulations of microtubules and regulate downstream microtubule-based functions. In this way, the tubulin modifications generate a “code” that can be read by microtubule-associated proteins in a manner analogous to how the histone code directs diverse chromatin functions. Here we review recent progress in understanding how the tubulin code is generated, maintained, and read by microtubule effectors.




REPORTS

Open Access Article

Neural Potential of a Stem Cell Population in the Hair Follicle

John L. Mignone, Jose L. Roig-Lopez, Natalia Fedtsova, Dustin E. Schones, Louis N. Manganas, Mirjana Maletic-Savatic, William M. Keyes, Alea A. Mills, Anatoli Gleiberman, Michael Q. Zhang and Grigori Enikolopov
Pages 2161 - 2170
http://dx.doi.org/10.4161/cc.6.17.4593
Abstract | PDF

The bulge region of the hair follicle serves as a repository for epithelial stem cells that can regenerate the follicle in each hair growth cycle and contribute to epidermis regeneration upon injury. Here we describe a population of multipotential stem cells in the hair follicle bulge; these cells can be identified by fluorescence in transgenic nestin-GFP mice. The morphological features of these cells suggest that they maintain close associations with each other and with the surrounding niche. Upon explantation, these cells can give rise to neurosphere-like structures in vitro. When these cells are permitted to differentiate, they produce several cell types, including cells with neuronal, astrocytic, oligodendrocytic, smooth muscle, adipocytic, and other phenotypes. Furthermore, upon implantation into the developing nervous system of chick, these cells generate neuronal cells in vivo. We used transcriptional profiling to assess the relationship between these cells and embryonic and postnatal neural stem cells and to compare them with other stem cell populations of the bulge. Our results show that nestin-expressing cells in the bulge of the hair follicle have stem cell-like properties, are multipotent, and can effectively generate cells of neural lineage in vitro and in vivo.

Open Access Article

By Blocking Apoptosis, Bcl-2 in p38-Dependent Manner Promotes Cell Cycle Arrest and Accelerated Senescence After DNA Damage and Serum Withdrawal

Anna Nelyudova, Nikolai D. Aksenov, Valery Pospelov and Tatiana Pospelova
Pages 2171 - 2177
http://dx.doi.org/10.4161/cc.6.17.4610
Abstract | PDF

E1A+ras-transformed rodent fibroblasts are unable to be arrested in the cell cycle and die by apoptosis in response to cytostatics, ionizing radiation (IR), or serum withdrawal. Overexpression of the human antiapoptotic gene bcl-2 suppresses apoptosis and induces reversible cell cycle arrest after IR or serum withdrawal and cell senescence after adriamycin treatment. Bcl-2-sustained adriamycin-induced cell senescence requires p38 MAPK, since the knockout of p38 MAPK abrogated anti-apoptotic and senescence-inducing effects of Bcl-2 in adriamycin-treated cells. Moreover, resistance to apoptosis and cell cycle arrest were not observed in p38 -/- E1A+ras+bcl-2-transformants following IR or serum deprivation. However, the pro-apoptotic effect of nocodazole in E1A+ras-transformed cells can not be prevented by Bcl-2 overexpression independently of the presence of p38 MAPK. These results allow us to conclude that p38 is necessary for Bcl-2-induced inhibition of apoptosis, induction of cell cycle arrest and accelerated senescence after DNA damage and serum starvation, but not after nocodazole treatment.

Open Access Article

Nutlin-3 inhibits the NFκB Pathway in a p53 Dependent Manner: Implications in Lung Cancer Therapy

Anwesha Dey, E.T. Wong, P. Bist, V. Tergaonkar and David Lane
Pages 2178 - 2185
http://dx.doi.org/10.4161/cc.6.17.4643
Abstract | PDF

Nutlins were identified as the first potent and specific small molecule Mdm2 antagonists that inhibit the p53- Mdm2 interaction. We show in this study that Nutlin-3 can downregulate TNFα induced activation of the NF-κB reporter in lung cancer cells. Activation of p53 dependent transcription is not compromised when Nutlin-3 is combined with TNFα. Instead, this combination treatment decreases cell viability in a p53 dependent manner. We show that Nutlin-3 strikingly inhibits the protein expression of NF-κB target genes ICAM-1 and MCP-1 while other targets like Bcl-xL and FLIP are not affected, thereby suggesting that the inhibition is promoter specific. This inhibition of ICAM-1 and MCP-1 by Nutlin-3 is again dependent on the p53 status in cells. Furthermore, we show that Nutlin-3 strongly inhibits protein expression of ICAM-1 and MCP-1 induced by IL1, another NF-κB activating stimuli. Nutlin-3 does not inhibit Akt phosphorylation, IκBα phosphorylation, IκBα degradation, p65 modification or p65 DNA binding in the cell lines tested. This study suggests the potential of Nutlin-3 as a bitargeted anti-cancer drug by simultaneously causing p53 activation and NF-κB suppression. It also suggests that Nutlin-3 could be evaluated for treatment of lung cancer as a single agent or in combination therapy by targeting its effect on ICAM-1 and MCP-1 which are known to be critical for cancer cell invasion, thereby downregulating tumor formation and metastasis. This study also suggests biomarkers of response for evaluation of Nutlin-3 in the clinic.

Open Access Article

A Novel Mechanism of E2F1 Regulation Via Nucleocytoplasmic Shuttling: Determinants of Nuclear Import and Export

Iordanka A. Ivanova, Alisa Vespa and Lina Dagnino
Pages 2186 - 2195
http://dx.doi.org/10.4161/cc.6.17.4650
Abstract | PDF

E2F1 is a transcription factor central for cell survival, proliferation, and repair following genomic insult. Depending on the cell type and conditions, E2F1 can induce apoptosis in transformed cells, behaving as a tumour suppressor, or impart growth advantages favouring tumour formation. The pleiotropic functions of E2F1 are a likely consequence of its ability to transcriptionally control a wide variety of target genes, and require tight regulation of its activity at multiple levels. Although sequestration of proteins to particular cellular compartments is a well-established regulatory mechanism, virtually nothing is known about its contribution to modulation of E2F1 target gene expression. We have examined the subcellular trafficking of E2F1 and, contrary to the widely held notion that this factor is constitutively nuclear, we now demonstrate that it is subjected to continuous nucleocytoplasmic shuttling. We have also defined two nuclear localization domains and a nuclear export region, which mediates CRM1-dependent transit out of the nucleus. The predominant subcellular location of E2F1 is likely determined by the balance between the activitiy of nuclear import and export domains, and can be modulated by differentiation stimuli in epidermal cells. Thus, we have identified a hitherto unrecognized mechanism to control E2F1 function through modulation of its subcellular localization.