Table of Contents

Volume 9, Issue 1

  January 1, 2010

  Pages 1 - 204

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EDITORIALS: CELL CYCLE FEATURES

Open Access Article

Cell polarity, Notch signaling and neurogenesis

Olga Ossipova and Sergei Y. Sokol
Pages 1 - 2
http://dx.doi.org/10.4161/cc.9.1.10357
Abstract | PDF

Comment on: Ossipova O, et al. Dev Cell 2009; 17:222-33.

Open Access Article

Enterotoxigenic Bacteroides fragilis (ETBF)-mediated colitis in Min (Apc^+/-) mice: a human commensal-based murine model of colon carcinogenesis

Franck Housseau and Cynthia L. Sears
Pages 3 - 5
http://dx.doi.org/10.4161/cc.9.1.10352
Abstract | PDF

Comment on: Wu S, et al. Nat Med 2009; 15:1016-22.

Open Access Article

Emerging role of FKBP51 in AKT kinase/protein kinase B signaling

Huadong Pei, Zhenkun Lou and Liewei Wang
Pages 6 - 7
http://dx.doi.org/10.4161/cc.9.1.10290
Abstract | PDF

Comment on: Pei H, et al. Cancer Cell 2009; 16:259-66.

Open Access Article

Cracking the code for compartment-specific dual functionality proteins in cancer: The case for CRKL

Michael G. Ozawa, Marina Cardó-Vila, Paul J. Mintz, Wadih Arap and Renata Pasqualini
Pages 8 - 9
http://dx.doi.org/10.4161/cc.9.1.10288
Abstract | PDF

Comment on: Mintz PJ, et al. Proc Natl Acad Sci USA 2009; 106:2182-7.

Open Access Article

Wnt signaling and specification of the respiratory endoderm

Ashley M. Goss and Edward E. Morrisey
Pages 10 - 11
http://dx.doi.org/10.4161/cc.9.1.10272
Abstract | PDF

Comment on: Goss AM, et al. Dev Cell 2009; 17:290-8.

Open Access Article

Real time with Caspase-2

Lisa Bouchier-Hayes and Douglas R. Green
Pages 12 - 13
http://dx.doi.org/10.4161/cc.9.1.10477
Abstract | PDF

Comment on: Bouchier-Hayes L, et al. Mol Cell 2009;35:830-40.

Open Access Article

Developmental strategies for evasion of Arf tumor suppression

Emmanuel J. Volanakis and Charles J. Sherr
Pages 14 - 15
http://dx.doi.org/10.4161/cc.9.1.10390
Abstract | PDF

Comment on: Volanakis EJ, et al. Blood 2009; 114:4451-9.

Open Access Article

A novel parkin-mediated transcriptional function links p53 to familial Parkinson’s disease

Cristina Alves da Costa and Frédéric Checler
Pages 16 - 17
http://dx.doi.org/10.4161/cc.9.1.10420
Abstract | PDF

Comment on: da Costa CA, et al. Nat Cell Biol 2009; In press.

Open Access Article

Mechanism of MAPK-targeted gene expression unraveled in plants

Andrea Pitzschke and Heribert Hirt
Pages 18 - 19
http://dx.doi.org/10.4161/cc.9.1.10329
Abstract | PDF

Comment on: Pitzschke A, et al. Proc Natl Acad Sci USA 2009; In press.

Open Access Article

Isogenic mutant human cells: A new tool for personalized cancer medicine

Federica Di Nicolantonio, Sabrina Arena, Margherita Gallicchio and Alberto Bardelli
Pages 20 - 21
http://dx.doi.org/10.4161/cc.9.1.10474
Abstract | PDF

Comment on: Di Nicolantonio F, et al. Proc Natl Acad Sci USA 2008;105:20864-9.




CELL CYCLE NEWS & VIEWS

Open Access Article

The specific roles of mitotic cyclins revealed

Mohammad M. Rahman and Edward Kipreos
Pages 22 - 27
http://dx.doi.org/10.4161/cc.9.1.10577
Abstract | PDF

Comment on:  van der Voet, et al. Cell Cycle 2009; In press.

Open Access Article

Cell death or survival: The complex choice of the Retinoblastoma tumor suppressor protein

Alessandra Ianari and Alberto Gulino
Pages 22 - 27
http://dx.doi.org/10.4161/cc.9.1.10586
Abstract | PDF

Comment on: Milet C, et al. Cell Cycle 2010; 9(1): In press

Open Access Article

Cdc48 connects with eIF3

Franziska Kriegenburg and Rasmus Hartmann-Petersen
Pages 22 - 27
http://dx.doi.org/10.4161/cc.9.1.10565
Abstract | PDF

Comment on: Int6 and Moe1 interact with Cdc48 to regulate ERAD and proper chromosome segregation. Otero JH, et al. Cell Cycle 2010; 9:In press.


Open Access Article

A novel role for Chk2 after DNA damage in mitosis?

Ailine Stolz and Holger Bastians
Pages 22 - 27
http://dx.doi.org/10.4161/cc.9.1.10579
Abstract | PDF

Comment on: Varmark, et al. Cell Cycle 2010; 9(2); In press

Open Access Article

New connections identify Sch9 as a central node in ribosome biosynthesis

Deborah Johnson
Pages 22 - 27
http://dx.doi.org/10.4161/cc.9.1.10566
Abstract | PDF

Comment on: Sch9 partially mediates TORC1 signaling to control ribosomal RNA synthesis. Wei Y, et al. Cell Cycle 2009; 8:In press.


Open Access Article

POPX adds to cell motility

Sheila Govind and Christine Hall
Pages 22 - 27
http://dx.doi.org/10.4161/cc.9.1.10735
Abstract | PDF

Comment on: Susila A, et al. Cell Cycle 2010; In this issue.




SPECIAL FEATURE

Open Access Article

The Physical Space of Science: The Neurosciences Institute and Skirkanich Hall

Tod Williams and Billie Tsien
Pages 28 - 31
http://dx.doi.org/10.4161/cc.9.1.10524
Abstract | PDF

This is the first in a series of articles that Landes Bioscience will pub­lish about the physical space where research takes place—the laboratories and classrooms where the science you read about in our journals is happening. Here we interviewed New York–based architects Tod Williams and Billie Tsien about two of their projects, The Neurosciences Institute in La Jolla and Skirkanich Hall at the University of Pennsylvania. We asked them, among other things, how they engaged scientists in the design process. Here is their response.




EXTRA VIEWS

Open Access Article

Vitamin D: Proteases, protease inhibitors and cancer

Silvia Álvarez-Díaz, María Jesús Larriba, Carlos López-Otín and Alberto Muñoz
Pages 32 - 37
http://dx.doi.org/10.4161/cc.9.1.10266
Abstract | PDF

The active vitamin D metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3, Calcitriol) is a major regulator of gene expression in higher organisms. Protein abundance is an endpoint of gene expression that results from the balance between induction and degradation and is essential for adequate cell function. Proteins are degraded by proteases whose activity is in turn controlled by a number of endogenous protease inhibitors. 1,25(OH)2D3 regulates several proteases and protease inhibitors in different cell types, putatively contributing to its regulatory effects of cell physiology. We have recently shown that 1,25(OH)2D3 strongly induces the expression of cystatin D, an inhibitor of several cysteine proteases of the cathepsin family. Cystatin D induction may contribute to the antitumor effect of 1,25(OH)2D3 against colon cancer by mechanisms that are both dependent and independent of cathepsin inhibition. Transcriptomic studies suggest that 1,25(OH)2D3 also modulates the function of the ubiquitin-proteasome system. Thus, proteases and protease inhibitors are candidates to mediate to a certain extent the complex action of 1,25(OH)2D3 in cancer cells.

Open Access Article

The roles of nitric oxide synthase and eIF2alpha kinases in regulation of cell cycle upon UVB-irradiation

Lei Wang, Yan Liu and Shiyong Wu
Pages 38 - 42
http://dx.doi.org/10.4161/cc.9.1.10268
Abstract | PDF

In response to ultraviolet light (UV)-induced damage, cells initiate cellular recovery mechanisms including activation of repair genes and redistribution of cell cycle phases. While most studies have focused on DNA damage-inducible transcriptional regulation of cell cycle checkpoints, translational regulation also plays an important role in control of cell cycle progression upon UV-irradiation. UV-irradiation activates two kinases, PERK and GCN2, which phosphorylate the alpha subunit of eukaryotic initiation factor 2 (eIF2α) and subsequently inhibit protein synthesis. We recently identified an upstream regulator, nitric oxide synthase (NOS), which controls the activation of both PERK and GCN2 upon UVB-irradiation. Our data suggested that UVB induces NOS activation and NO• production, which reacts with superoxide (O2•−) to form peroxynitrite (ONOO−) and activate PERK. The NO• production also leads to L-Arg depletion and GCN2 activation. The elevation of nitric oxide and activation of PERK/GCN2 have been shown to play roles in regulation of cell cycle upon UVB irradiation. In the present study, we show that the cell cycle phases were redistributed by inhibition of NOS activation or reduction of oxidative stress upon UVB irradiation, indicating the roles of NO• and its oxidative products in regulation of cell cycle. We also demonstrate that both PERK and GCN2 were involved in regulation of cell cycle upon UVB-irradiation, but the regulation is independent of eIF2α phosphorylation. While the mechanism for UVB-induced cell cycle control is yet to be unraveled, we here discuss the differential roles of NOS, PERK and GCN2 in regulation of cell cycle upon UVB-irradiation.

Open Access Article

Opening the DNA repair toolbox: Localization of DNA double strand breaks to the nuclear periphery

Pranav Oza and Craig L. Peterson
Pages 43 - 49
http://dx.doi.org/10.4161/cc.9.1.10317
Abstract | PDF

Efficient repair of DNA double strand breaks is essential for cells to avoid increased mutation rates, genomic instability, and even cell death. Consequently, cells have evolved multiple mechanisms for rapidly repairing these DNA lesions, including error-free homologous recombination as well as error-prone pathways such as nonhomologous end-joining. What happens to DSBs that are repaired inefficiently or not at all? Recently, several studies in budding yeast have shown that these more recalcitrant DSBs are localized to the nuclear periphery through interactions between the nuclear envelope protein, Mps3, and proteins associated with DSB chromatin. Why these DSBs are tethered to the nuclear periphery is still not clear, though the current view is that alternative repair pathways may be activated at the periphery in a final attempt to repair the lesion. In this Extra-view, we discuss these recent reports, and we show that the Est1 component of the telomerase machinery plays an essential role in anchoring DSB chromatin to the nuclear envelope protein, Mps3.

Open Access Article

During hypoxia, HUMMR joins the mitochondrial dance

Yan Li and David A. Rempe
Pages 50 - 57
http://dx.doi.org/10.4161/cc.9.1.10318
Abstract | PDF

Mitochondrial distribution is integrally related to cellular function. Highly polarized cells, such as neurons, likely depend on mitochondrial transport to maintain proper synaptic function and neurite plasticity. In some cases, mitochondrial transport is also required for cellular migration and proper calcium signaling in non-neuronal cells. Over the past few years, much progress has been made in identifying proteins that control mitochondrial transport and distribution. Miro and Milton, which are two outer mitochondrial membrane proteins, tether mitochondria to kinesin motor proteins. Our recent work identified a novel protein, HUMMR, which interacts with Miro. While present in normoxia, HUMMR protein abundance is markedly induced by hypoxia through a HIF-1 dependent mechanism. Knock down of HUMMR function diminishes the number of mitochondria in the axon, an effect that was more prominent in neurons exposed to hypoxia. Interestingly, in hypoxic neurons, knock down of HUMMR also diminished the number of anterograde moving mitochondria, but increased the number of retrograde moving mitochondria. Thus, HUMMR is a protein which biases mitochondrial movement in the anterograde direction in response to hypoxia. The implication for this biased transport of mitochondria during hypoxia on neuronal function and viability is yet to be discerned. Regardless, since hypoxia is prominent during ischemia and in solid tumors, HUMMR likely contributes to mitochondrial distribution under these conditions. As such, HUMMR may influence cellular function that is dependent upon the correct mitochondrial localization.

Open Access Article

The multiple roles of Bub1 in chromosome segregation during mitosis and meiosis

Francesco Marchetti and Sundaresan Venkatachalam
Pages 58 - 63
http://dx.doi.org/10.4161/cc.9.1.10348
Abstract | PDF

Aneuploidy, any deviation from an exact multiple of the haploid number of chromosomes, is a common occurrence in cancer and represents the most frequent chromosomal disorder in newborns. Eukaryotes have evolved mechanisms to assure the fidelity of chromosome segregation during cell division that include a multiplicity of checks and controls. One of the main cell division control mechanisms is the spindle assembly checkpoint (SAC) that monitors the proper attachment of chromosomes to spindle fibers and prevents anaphase until all kinetochores are properly attached. The mammalian SAC is composed by at least 14 evolutionary-conserved proteins that work in a coordinated fashion to monitor the establishment of amphitelic attachment of all chromosomes before allowing cell division to occur. Among the SAC proteins, the budding uninhibited by benzimidazole protein 1 (Bub1), is a highly conserved protein of prominent importance for the proper functioning of the SAC. Studies have revealed many roles for Bub1 in both mitosis and meiosis, including the localization of other SAC proteins to the kinetochore, SAC signaling, metaphase congression and the protection of the sister chromatid cohesion. Recent data show striking sex specific differences in the response to alterations in Bub1 activity. Proper Bub1 functioning is particularly important during oogenesis in preventing the generation of aneuploid gametes that can have detrimental effects on the health status of the fetus and the newborn. These data suggest that Bub1 is a master regulator of SAC and chromosomal segregation in both mitosis and meiosis. Elucidating its many essential functions in regulating proper chromosome segregation can have important consequences for preventing tumorigenesis and developmental abnormalities.

Open Access Article

Inhibition of cancer progression by rifampicin: Involvement of antiangiogenic and anti-tumor effects

Masayoshi Shichiri and Yujiro Tanaka
Pages 64 - 68
http://dx.doi.org/10.4161/cc.9.1.10354
Abstract | PDF

Very recently, we reported that an antituberculous agent, rifampicin, exerts potent inhibitory effects on hepatic tumors when administered orally at low doses. The in vitro effects of rifampicin to rapidly downregulate angiogenesis- and mitogenesis-related genes in cultured endothelial cells are reminiscent of endostatin, one of the most well-studied angiogenesis inhibitors. However, rifampicin at the expected hepatobiliary concentrations after low oral doses showed more complete antiproliferative effects on endothelial cells, which make rifampicin favorable as an adjunct anticancer regimen. Since rifampicin undergoes hepatic accumulation resulting from the enterohepatic circulation, it may be especially beneficial for targeting hepatobiliary tumors. In the present paper, we extend our observations on the antiangiogenic properties of rifampicin and further elaborate on its direct antitumor effects on a variety of human cancer-derived cells.

Open Access Article

TERRA, CpG methylation, and telomere heterochromatin: Lessons from ICF syndrome cells

Zhong Deng, Amy E. Campbell and Paul M. Lieberman
Pages 69 - 74
http://dx.doi.org/10.4161/cc.9.1.10358
Abstract | PDF

Self-reinforcing negative feedback loops are commonly observed in biological systems. RNA-mediated negative feedback loops have been described in the formation of heterochromatin at centromeres in fission yeast and the inactive X chromosome in mammalian cells. The telomere repeat-containing RNA (TERRA) has also been implicated in the formation of telomeric heterochromatin through a self-reinforcing negative feedback loop. In cells derived from human ICF syndrome, TERRA levels are abnormally elevated and telomeres are abnormally shortened. We now show that telomere heterochromatin is also abnormal in ICF cells. We propose that ICF cells fail to reinforce the TERRA-dependent negative feedback loop as a result of the inability to establish heterochromatin at subtelomeres. This failure is likely due to the lack of DNMT3b and DNA methylation, which is a genetic lesion associated with ICF syndrome. Failure of this feedback mechanism leads to catastrophic telomere dysfunction and chromosome instability.

Open Access Article

HIF-1α dysfunction in diabetes

Hariharan Thangarajah, Ivan N. Vial, Raymon H. Grogan, Dachun Yao, Yubin Shi, Michael Januszyk, Robert D. Galiano, Edward I. Chang, Michael G. Galvez, Jason P. Glotzbach, Victor W. Wong, Michael Brownlee and Geoffrey C. Gurtner
Pages 75 - 79
http://dx.doi.org/10.4161/cc.9.1.10371
Abstract | PDF

Diabetic wounds are a significant public health burden, with slow or non-healing diabetic foot ulcers representing the leading cause of non-traumatic lower limb amputation in developed countries. These wounds heal poorly as a result of compromised blood vessel formation in response to ischemia. We have recently shown that this impairment in neovascularization results from a high glucose-induced defect in transactivation of hypoxia-inducible factor-1α (HIF-1α), the transcription factor regulating vascular endothelial growth factor (VEGF) expression. HIF-1 dysfunction is the end result of reactive oxygen species-induced modification of its coactivator p300 by the glycolytic metabolite methylglyoxal. Use of the iron chelator-antioxidant deferoxamine (DFO) reversed these effects and normalized healing of humanized diabetic wounds in mice. Here, we present additional data demonstrating that HIF-1α activity, not stability, is impaired in the high glucose environment. We demonstrate that high glucose-induced impairments in HIF-1α transactivation persist even in the setting of constitutive HIF-1α protein overexpression. Further, we show that high glucose-induced hydroxylation of the C-terminal transactivation domain of HIF-1α (the primary pathway regulating HIF-1α/p300 binding) does not alter HIF-1α activity. We extend our study of DFO’s therapeutic efficacy in the treatment of impaired wound healing by demonstrating improvements in tissue viability in diabetic mice with DFO-induced increases in VEGF expression and vascular proliferation. Since DFO has been in clinical use for decades, the potential of this drug to treat a variety of ischemic conditions in humans can be evaluated relatively quickly.




PERSPECTIVE

Open Access Article

Ligand-driven activation of the Notch pathway in T-all and solid tumors: Why Not(ch)?

Stefano Indraccolo, Sonia Minuzzo, Massimo Masiero and Alberto Amador
Pages 80 - 85
http://dx.doi.org/10.4161/cc.9.1.10346
Abstract | PDF

The Notch pathway is an evolutionally conserved cell-cell interaction signaling system involved in several key aspects of cell life, ranging from differentiation and proliferation to apoptosis. As such, it plays an important role in development, homeostasis, angiogenesis and various diseases. Over-activation of the Notch pathway has often been reported in cancer, leading to a variety of effects including increased proliferation, protection from apoptosis and maintenance of cancer initiating cells. Additionally, this signaling pathway has also been involved in tumor angiogenesis. The clearest example of oncogenic Notch signaling is observed in T acute lymphoblastic leukemia (T-ALL), an aggressive neoplasm of immature T-cells, due to genetic alterations leading to ligand-independent increased Notch1 receptor signaling. In solid tumors, however, extrinsic regulation through canonical cell-cell interactions appears to drive activation of the pathway. We recently found that triggering of Notch3 signaling by DLL4 expressed on angiogenic endothelial cells promotes escape of T-ALL cells from tumor dormancy in a xenograft model. This observation discloses un unsuspected role for ligand-dependent regulation of Notch receptors in T-ALL cells, suggesting that blocking extrinsic Notch activation by anti-DLL4 or other ligand-targeted drugs could represent a novel therapeutic approach for this aggressive malignancy.




REVIEWS

Open Access Article

Tumor suppression by ARF: Gatekeeper and caretaker

Carmen Dominguez-Brauer, Patrick M. Brauer, Yi-Ju Chen, Julia Pimkina and Pradip Raychaudhuri
Pages 86 - 89
http://dx.doi.org/10.4161/cc.9.1.10350
Abstract | PDF

ARF is a vital tumor suppressor and its loss contributes significantly to cancer. The frequency in which ARF is mutated, deleted or silenced is second to the loss of p53. The most documented and widely accepted activity of ARF is mediated through its activation of the p53 transcriptional program by inhibiting MDM2 function. However, several lines of evidence have surfaced demonstrating that ARF possesses p53-independent functions. One of these p53 independent functions is ARF’s regulation of the E2F family. The E2F/DP transcription factor is critical for cell cycle progression. The balance between activator and repressor E2Fs regulates the expression of E2F target genes and thus cell proliferation as well as other cellular functions such as checkpoint, chromosome assembly and repair. Through its ability to bind directly to DP1, ARF can cause dissociation of both activator and repressor E2Fs. While the regulation of the activator E2Fs is related to cell cycle arrest, there is evidence that the regulation of the repressors, E2F4 and E2F5, is significant in maintaining genomic stability.

Open Access Article

The long unwinding road: XPB and XPD helicases in damaged DNA opening

Valentyn Oksenych and Frédéric Coin
Pages 90 - 96
http://dx.doi.org/10.4161/cc.9.1.10267
Abstract | PDF

The mammalian nucleotide excision repair (NER) pathway removes dangerous bulky adducts from genomic DNA. Failure to eliminate these lesions can lead to oncogenesis, developmental abnormalities and accelerated ageing. TFIIH is a central NER factor that opens the damaged DNA through the action of its two helicases (XPB and XPD) prior to incision. Here we review our recently published data that suggest specific and distinct roles for these two helicases in NER. We also discuss the regulation of XPB and XPD enzymatic activities within TFIIH and repair complexes, and show that mutations impeding enzyme-regulator interaction contribute to genetic disorders. Understanding the fundamental molecular mechanism regulating NER is a crucial aspect of cancer therapy since the resistance to chemotherapy treatment relies on the capacities of the cell to eliminate drug-induced DNA lesions.




REPORTS

Open Access Article

The Drosophila retinoblastoma protein induces apoptosis in proliferating but not in post-mitotic cells

Cécile Milet, Aurore Rincheval-Arnold, Bernard Mignotte and Isabelle Guénal
Pages 97 - 103
http://dx.doi.org/10.4161/cc.9.1.10251
Abstract | PDF

The retinoblastoma protein, pRb, plays important roles in many processes implicated in cell fate decisions, including cell cycle, differentiation and apoptosis. In cell cycle regulation, pRb interacts principally with the E2F transcription factor family members to inhibit the transcription of many genes controlling cell cycle progression. In this study, we focused on the role of pRb in apoptosis, which is much less clear than its role in cell cycle regulation. Indeed, pRb has been found to be either pro- or anti-apoptotic. To clarify how the proliferative status of the cells impacts the role of pRb in apoptosis, we used Drosophila to induce RBF (the pRb fly homologue) expression in different cellular and developmental contexts. We found that RBF expression induces apoptosis in different proliferative tissues in a caspase-dependent manner, whereas this effect was not observed in differentiated post-mitotic cells. Furthermore, RBF-induced apoptosis in proliferating cells was inhibited by co-expression of dE2F1, an antagonistic partner of RBF in cell cycle regulation. These results are in agreement with the view that the apoptotic properties of pRb are tightly linked to, and are probably a consequence of, an effect on cell cycle progression. Moreover, we show for the first time that RBF has a direct anti-apoptotic effect on Dmp53-induced cell death in post-mitotic cells only. Taken together, these data clearly show that RBF can exert a dual role in the control of apoptotic processes, and that its properties depend on the proliferative status of the cells.

Open Access Article

Genome wide identification of Plasmodium falciparum helicases: A comparison with human host

Renu Tuteja
Pages 104 - 120
http://dx.doi.org/10.4161/cc.9.1.10241
Abstract | PDF

Helicases are enzymes which catalyze the unwinding of nucleic acid substrate in an energy-dependent manner.  These are characterized by the presence of nine well defined conserved motifs and are essential for almost all the processes involving nucleic acids.  Plasmodium falciparum causes the most virulent form of malaria.  The control of malaria is becoming complicated due to the spread of resistance of both the mosquito vector and the parasite to insecticides and anti-malarial drugs.  Helicases could be used as feasible drug target for control of malaria.  The P. falciparum genome is completely sequenced but the annotation is still in progress.  To identify members of various well defined helicase families, I used the bioinformatics approach and helicase domain sequences to search the P. falciparum genome sequence database.  In addition to the homologues for a number of human helicases, some novel parasite specific helicases were also identified.  I describe the members of DEAD-box, DEAH box, RuvB, Superkiller family, RecQ and repair helicases form P. falciparum.  The detailed studies of these helicases will help in identifying a specific enzyme, which could be used as potential target to control the replication and transmission of the malaria parasite.

Open Access Article

Single cell nanoparticle tracking to model cell cycle dynamics and compartmental inheritance

Rachel J. Errington, Martyn R. Brown, Oscar Silvestre, Kerenza L. Njoh, Sally C. Chappell, Imtiaz Khan, Paul Rees, Steve P. Wilks, Paul J. Smith and Huw D. Summers
Pages 121 - 130
http://dx.doi.org/10.4161/cc.9.1.10246
Abstract | PDF

Single cell encoding with quantum dots as live cell optical tracers for deriving proliferation parameters has been developed using modelling to investigate cell cycle and proliferative outputs of human osteosarcoma cells undergoing mitotic bypass and endocycle routing. A computer-based simulation of the evolving cell population provides information on the dilution and segregation of nanoparticle dose cell by cell division and allows quantitative assessment of patterns of division, at both single cell and including whole population level cell cycle routing, with no a-priori knowledge of the population proliferation potential. The output therefore provides a unique mitotic distribution function that represents a convolution of cell cycle kinetics (cell division) and the partitioning coefficient for the labelled cell compartment (daughter-daughter inheritance or lineage asymmetry). The current study has shown that the cellular quantum dot fluorescence reduced over time as the particles were diluted by the process of cell division and had the properties of a non-random highly asymmetric event. Asymmetric nanoparticle segregation in the endosomal compartment has major implications on cell-fate determining signaling pathways and could lead to an understanding of the origins of unique proliferation and drug-resistance characteristics within a tumour cell lineage.

Open Access Article

Interferon-a2b induces p21^cip1/waf1 degradation and cell proliferation in HeLa cells

Ken Ota, Tomoh Matsumiya, Hirotake Sakuraba, Tadaatsu Imaizumi, Hidemi Yoshida, Shogo Kawaguchi, Shinsaku Fukuda and Kei Satoh
Pages 131 - 139
http://dx.doi.org/10.4161/cc.9.1.10250
Abstract | PDF

Type I interferons (IFNs) are a family of cytokines that exhibit various biological activities.  Besides their roles in immune response, IFNs have been known to modulate cell proliferation and to induce apoptosis.  Thus, IFNs are used as an anti-tumor agent against certain types of cancer, but it is unclear why many other cancers are not influenced by IFNs.  Here, we found that IFN-a2b, a subfamily of IFN-a, enhanced proliferation of HeLa cells, a cell line derived from human cervical cancer.  IFN-a2b was rather inhibitory on the growth of other types of cervical cancer cells including those positive for HPV.  Among the proliferation- and the apoptosis-related genes, p21^cip1/waf1 (p21) was upregulated by IFN-a2b, whereas p53, p27 or BCL-2 associated X protein (BAX) was not affected.  IFN-a2b did not alter promoter activities of p21 but did prolong the decay of p21 mRNA.  In contrast, the level of p21 protein was lowered by IFN-a2b, and half-life analysis of p21 protein revealed that IFN-a2b enhances p21 protein instability in HeLa cells.  Pretreatment of the cells with MG132, a proteasome inhibitor, abolished the IFN-a2b-mediated p21 degradation, suggesting that IFN-a2b accelerated the ubiquitin-proteasome dependent degradation of p21.  Consistent with these results, IFN-a2b increased S-phase cell cycle distribution in HeLa cells.  In addition, IFN-a2b liberated the cells from G1-phase arrest by 5-fluorouracil (5-FU) and from G2-phase arrest by paclitaxel.  These results provide a novel role of Type I IFNs in cell cycle regulation and may define an importance of individualized IFN-based therapy against specific types of cancer.

Open Access Article

Induction of papillary carcinoma in human ovarian surface epithelial cells using combined genetic elements and peritoneal microenvironment

Jingfang Zheng, Imelda Mercado-Uribe, Daniel G. Rosen, Bin Chang, Peishu Liu, Gong Yang, Anais Malpica, Honami Naora, Nelly Auersperg, Gordon B. Mills, Robert C. Bast and Jinsong Liu
Pages 140 - 146
http://dx.doi.org/10.4161/cc.9.1.10264
Abstract | PDF

Papillary differentiation is one of the most common histological features of ovarian cancer, although the underlying mechanism that leads to such differentiation is not known. We hypothesized that human ovarian surface epithelial cells can be transformed into carcinoma with papillary differentiation by overexpressing HER2/neu in these cells. Mice were injected either subcutaneously or intraperitoneally with two immortalized human ovarian surface epithelial cell lines after enforced expression of HER-2/neu. Mice subcutaneously injected with tumor cells from either the T29Nt or T80Nt developed undifferentiated carcinomas. In contrast, mice injected intraperitoneally with T29Nt cells developed papillary carcinoma, and those injected intraperitoneally with T80Nt cells developed undifferentiated carcinoma. Our results demonstrate that ovarian surface epithelial cells can develop into papillary carcinoma in mice, and that the induction of papillary differentiation depends not only on specific genetic modifications but also on the tumor microenvironment and epithelial cell type from ovary from different patients.

Open Access Article

Int6 and Moe1 interact with Cdc48 to regulate ERAD and proper chromosome segregation

Joel H. Otero, Jinfeng Suo, Colin Gordon and Eric C. Chang
Pages 147 - 161
http://dx.doi.org/10.4161/cc.9.1.10312
Abstract | PDF

Int6/eIF3e is implicated in tumorigenesis, but its molecular functions remain unclear. We have studied its fission yeast homolog Yin6, reporting that it regulates proteolysis by controlling the assembly/localization of proteasomes, and binds directly to another conserved protein, Moe1. In the present study, we isolated Cdc48 as a Moe1-binding protein from a yeast two-hybrid screen, and confirmed biochemically that they form a stable complex in fission yeast. Overexpressing Moe1 or Yin6 partially rescued phenotypes of cdc48 mutants; conversely, overexpressing Cdc48 partially rescued phenotypes of moe1 or yin6 mutants. Mutants defective in both Cdc48 and the Yin6-Moe1 complex showed growth defects that were far more severe than either alone. These double mutants were severely deficient in endoplasmic reticulum associated degradation (ERAD), as they were hypersensitive to accumulation of misfolded proteins. In addition, their chromosomes showed frequent defects in spindle attachment and segregation — these mitotic defects correlated with Ase1 and Bir1/survivin mislocalization. These results suggest that Cdc48, Yin6, and Moe1 act in the same protein complex to concertedly control ERAD and chromosome segregation. Many of these properties are evolutionarily conserved in humans, since human Cdc48 rescued the lethality of the yeast cdc48∆ mutant, and Int6 and Moe1/eIF3d bind Cdc48 in human cells.

Open Access Article

Yes-associated protein 1 regulates the stability of ΔNp63α

Aditi Chatterjee, Tanusree Sen, Xiaofei Chang and David Sidransky
Pages 162 - 167
http://dx.doi.org/10.4161/cc.9.1.10321
Abstract | PDF

Regulation of ΔNp63α can be achieved at the transcriptional and post-translational levels, with the latter being greatly influenced by external stimuli such as DNA damaging agents. In this present study, we demonstrated that ΔNp63α physical interacts with Yes-associated protein 1 (Yap1). Ectopic expression of Yap1 decreased the stability and the half-like of ΔNp63α and resulted in ubiquitin-dependent degradation of ΔNp63α. Further, the cisplatin mediated degradation of ΔNp63α is attenuated with the down-regulation of Yap1. Thus, our results strongly suggest that Yap1 plays a role in the regulation of endogenous ΔNp63α levels and is likely to contribute to the regulation of ΔNp63α, in physiological conditions.

Open Access Article

Processing of O⁶-methylguanine into DNA double-strand breaks requires two rounds of replication whereas apoptosis is also induced in subsequent cell cycles

Steve Quiros, Wynand P. Roos and Bernd Kaina
Pages 168 - 178
http://dx.doi.org/10.4161/cc.9.1.10363
Abstract | PDF

The DNA adduct O⁶-methylguanine (O⁶MeG) induced by environmental genotoxins and anticancer drugs is a highly mutagenic, genotoxic and apoptotic lesion. Apoptosis induced by O⁶MeG requires mismatch repair (MMR) and proliferation. Models of O⁶MeG-triggered cell death postulate that O⁶MeG/T mispairs activate MMR giving rise to either direct genotoxic signaling or secondary lesions that trigger apoptotic signaling in the 2nd replication cycle. To test these hypotheses, we used a highly synchronized cell system competent and deficient for the repair of O⁶MeG adducts, which were induced by the S_N1 methylating agent N-methyl-N’-nitro-N-nitrosoguanidine (MNNG). We show that DNA double-strand breaks (DSBs) are formed in response to O⁶MeG at high level in the 2nd S/G2-phase of the cell cycle. This is accompanied by ATR and Chk1 phosphorylation, G2/M arrest and late caspase activation. Although cells undergo apoptosis out of the 2nd G2/M-phase, the majority of them recovers and undergoes apoptosis after passing through additional replication cycles. The late apoptotic effects were completely abolished by O⁶-methylguanine-DNA methyltransferase, indicating that non-repaired O6MeG is carried over into subsequent generations, eliciting there a late apoptotic response. We also demonstrate that with a low, non-toxic dose of MNNG the passage of cells through the 1st and 2nd S-phase is not delayed, although the dose is able to induce excessive sister chromatid exchanges. This suggests that a significant amount of O⁶MeG can be tolerated by recombination, which is a fast process preventing from S-phase blockage, DSB formation and cell death.

Open Access Article

The POPX2 phosphatase regulates cancer cell motility and invasiveness

Agatha Susila, Hei Chan, Andrew Xiong-Wen Loh, Hui-Qun Phang, Ee Tsin Wong, Vinay Tergaonkar and Cheng-Gee Koh
Pages 179 - 187
http://dx.doi.org/10.4161/cc.9.1.10406
Abstract | PDF

Rho GTPases play major roles in the regulation of actin cytoskeleton, cell movement and cell cycle. PAK, one of the effector kinases of these small GTPases, has long been associated with different types of cancer. Therefore, it is likely that deregulation of PAK activity or expression may contribute to the development of cancer. POPX2, a PP2C serine/threonine phosphatase, is known to dephosphorylate PAK and down regulate its activity. We find that POPX2 is expressed in a wide variety of tumour cell lines, the levels being highest in the more invasive MDA-MB-231 and lowest in the non-invasive MCF7 breast cancer lines. We show that silencing of POPX2 reduces the amount of stress fibres and focal adhesions in both cells lines. Interestingly, POPX2 deficiency dramatically reduces cell motility and invasiveness in MDA-MB-231 cells, and cell motility in MCF7 cells. Conversely, overexpression of POPX2 in MDA-MB-231 and MCF7 cells increased their motility. The silencing of POPX2 also inhibits the expression of beta1 integrin implying that POPX2 may modulate cell attachment to the extra-cellular matrix, as reflected in diminished initial colonization of POPX2 knockdown cells in nude mice. Based on these results, we propose a mechanism by which POPX2 regulates the invasive behavior of the cells.

Open Access Article

Metformin extends life span of HER-2/neu transgenic mice and in combination with melatonin inhibits growth of transplantable tumors in vivo

Vladimir N. Anisimov, Peter A. Egormin, Tatiana S. Piskunova, Irina G. Popovich, Margarita L. Tyndyk, Maria N. Yurova, Mark A. Zabezhinski, Ivan V. Anikin, Arseniy S. Karkach and Alexey A. Romanyukha
Pages 188 - 197
http://dx.doi.org/10.4161/cc.9.1.10407
Abstract | PDF

Population studies have shown that treatment with the antidiabetic biguanide metformin significantly reduced cancer risk. In our animal studies, metformin delayed the onset of mammary adenocarcinoma (MAC) in transgenic HER-2/neu mice but not the onset of spontaneous mammary tumors in female SHR mice. Pineal hormone also inhibits mammary carcinoma development in HER2/neu transgenic mice as well as in female SHR mice. Here we demonstrated that a combination of metformin and melatonin significantly inhibits growth of transplanted tumors in mice. Metformin (1.2 mg/ml in drinking water) increased mean life span by 8% and MAC latency by 13.2% (p<0.05) in HER2/neu mice. The treatment with melatonin alone (2 mg/L in drinking water during the night time) or combined treatment with metformin (0.5 mg/ml in drinking water during the day time) + melatonin (2 mg/L in drinking water during the night time) did not influence mammary carcinogenesis in the mice. The treatment metformin alone inhibited the growth of transplantable HER2 mammary carcinoma in FVB/N male mice by 46% at the 45th day after transplantation (p<0.001). The combined treatment with metformin + melatonin significantly suppressed tumor growth (by 40%, p< 0.001). These results suggest that metformin may be useful in prevention and treatment of breast cancer.




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Open Access Article

Interaction between Rae1 and Cohesin subunit SMC1 is required for proper spindle formation

Richard W. Wong
Pages 198 - 200
http://dx.doi.org/10.4161/cc.9.1.10431
PDF

Open Access Article

TOS1 is circularly permuted 1,3-β-glucanase

Kamil Steczkiewicz, Lukasz Knizewski, Leszek Rychlewski and Krzysztof Ginalski
Pages 201 - 204
http://dx.doi.org/10.4161/cc.9.1.10510
PDF