Table of Contents

Volume 10, Issue 19

  October 1, 2011

  Pages 3211 - 3408

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 Issue Catalogue (MARC XML)

EDITORIALS: CELL CYCLE FEATURES

Open Access Article

Senescence-associated microRNAs linked to tumorigenesis

Subramanya Srikantan, Myriam Gorospe and Kotb Abdelmohsen
Pages 3211 - 3212
http://dx.doi.org/10.4161/cc.10.19.17050
Abstract | PDF

Comment on: Marasa BS, et al. Aging 2010; 2:333-43.

Open Access Article

Elite control of HIV: p21 (waf-1/cip-1) at its best

Xu G. Yu and Mathias Lichterfeld
Pages 3213 - 3214
http://dx.doi.org/10.4161/cc.10.19.17051
Abstract | PDF

Comment on: Chen H, et al. J Clin Invest 2011; 121:1549-60.

Open Access Article

LSD1 and pluripotency: A new player in the network

Antonio Adamo, Maria J. Barrero and Juan Carlos Izpisua Belmonte
Pages 3215 - 3216
http://dx.doi.org/10.4161/cc.10.19.17052
Abstract | PDF

Comment on: Adamo A, et al. Nat Cell Biol 2011; 13:652-60.

Open Access Article

Recognition of centromeric histone variant CenH3s by their chaperones: Structurally conserved or not

Yawen Bai, Zheng Zhou, Hanqiao Feng and Bing-Rui Zhou
Pages 3217 - 3218
http://dx.doi.org/10.4161/cc.10.19.17077
Abstract | PDF

Comment on: Zhou et al. Nature 2011; 47:234-237, Hu et al. Genes Dev 2011; 25:901-6 and Cho et al. Proc Natl Acad Sci USA 2011; 108:9367-71.

Open Access Article

MicroRNA regulation masters basal transcription: Clash of the Titans

Maximiliano M. Portal
Pages 3219 - 3220
http://dx.doi.org/10.4161/cc.10.19.17078
Abstract | PDF

Comment on: Portal MM. Proc Natl Acad Sci USA 2011; 108:8686-91.

Open Access Article

From the nucleus to the mitochondria and back: The odyssey of a multitask STAT3

Marco Demaria and Valeria Poli
Pages 3221 - 3222
http://dx.doi.org/10.4161/cc.10.19.17379
Abstract | PDF

Comment on: Demaria M, et al. Aging (Albany NY) 2010; 2:823-842.

Open Access Article

Phosphorylated H2Ax is not an unambiguous marker for DNA double-strand breaks

James E. Cleaver, Luzviminda Feeney and Ingrid Revet
Pages 3223 - 3224
http://dx.doi.org/10.4161/cc.10.19.17448
Abstract | PDF

Comment on: Revet I, et al. Proc Natl Acad Sci USA. 2011; 108:8663-7.

Open Access Article

Stuck in a balancing act: Histone methyltransferase activity of KMT1A traps alveolar rhabdomyosarcomas in an undifferentiated state

Kyle L. MacQuarrie and Stephen J. Tapscott
Pages 3225 - 3226
http://dx.doi.org/10.4161/cc.10.19.17451
Abstract | PDF

Comment on: Lee, et al. Cancer Res 2011; 71:3921-31.




CELL CYCLE NEWS & VIEWS

Open Access Article

MRE11 and ATM AKTivate pro-survival signaling

Sarah E. Golding and Kristoffer Valerie
Pages 3227 - 3236
http://dx.doi.org/10.4161/cc.10.19.17048
Abstract | PDF

Comment on: Fraser, M, et al. Cell Cycle 2011; 10:2218-32.

Open Access Article

The HIF-1α-c-Myc pathway and tumorigenesis: Evading the apoptotic gate-keeper

Nicole Fer and Giovanni Melillo

http://dx.doi.org/10.4161/cc.10.19.17049
Abstract | PDF

Comment on: Hayashi M, et al. Cell Cycle 2011; 10:2364–72

Open Access Article

Cyclooxygenase (COX)-1 takes control of adult hippocampal neurogenesis

Stefano Pluchino and Clara Alfaro-Cervello

http://dx.doi.org/10.4161/cc.10.19.17079
Abstract | PDF

Comment on: Russo I, et al. Cell Cycle 2011; 10:2218-32.

Open Access Article

DNA double-strand breaks make bedfellows of ATM and AKT

Bipasha Mukherjee and Sandeep Burma

http://dx.doi.org/10.4161/cc.10.19.17080
Abstract | PDF

Comment on: Fraser M, et al. Cell Cycle 2011; 10:2218-32.

Open Access Article

Autophagic tumor stroma: A biofuel for cancer growth

Renato V. Iozzo

http://dx.doi.org/10.4161/cc.10.19.17124
Abstract | PDF

Comment on: Castello-Cros R, et al. Cell Cycle 2011; 10:2021-34.

Open Access Article

miR-27a regulation of SCF^Fbw7 in cell division control and cancer

Charles Spruck

http://dx.doi.org/10.4161/cc.10.19.17125
Abstract | PDF

Comment on: Lerner M, et al. Cell Cycle 2011; 10:2172-83.

Open Access Article

Taccalonolides: A microtubule stabilizer poses a new puzzle with old pieces

Dan L. Sackett and Tito Fojo

http://dx.doi.org/10.4161/cc.10.19.17126
Abstract | PDF

Comment on: Risinger AL, et al. Cell Cycle 2011; 10:2162-71.

Open Access Article

Checking before changing: Cell cycle checkpoints inhibit muscle differentiation

Jean Y.J. Wang

http://dx.doi.org/10.4161/cc.10.19.17127
Abstract | PDF

Comment on: Simonatto M, et al. Cell Cycle 2011; 10:2355-63.

Open Access Article

Novel role of Wip1 in p53-mediated cell homeostasis under non-stress conditions

Jin Zhang and Xinbin Chen

http://dx.doi.org/10.4161/cc.10.19.17128
Abstract | PDF

Comment on: Park HK, et al. Cell Cycle 2011; 10:2574-82.

Open Access Article

Lamins, guardians of the soma and the genome

José M.P. Freije and Alberto M. Pendás

http://dx.doi.org/10.4161/cc.10.19.17129
Abstract | PDF

Comment on: Redwood AB, et al. Cell Cycle 2011; 10:2549-60.




PERSPECTIVES

Open Access Article

A novel role of hydrogen peroxide in Kaposi sarcoma-associated herpesvirus reactivation

Fengchun Ye and Shou-Jiang Gao
Pages 3237 - 3238
http://dx.doi.org/10.4161/cc.10.19.17299
Abstract | PDF

Reactivation of Kaposi sarcoma-associated herpesvirus (KSHV) from latency for lytic replication plays a pivotal role in the development of KS tumors. However, the physiological factors of KSHV reactivation in KS patients remain undefined. Two recent studies independently discovered that the reactive oxygen species (ROS) H2O2 induces KSHV reactivation in latently infected cells, which can be inhibited by H2O2-specific antioxidants. H2O2 not only directly induces KSHV reactivation but also is involved in spontaneous lytic replication as well as reactivation stimulated by TPA, hypoxia, and cytokines. Furthermore, in a xenograft-based primary effusion lymphoma (PEL) mouse model, in vivo KSHV reactivation is also H2O2-dependent and can be suppressed by antioxidants. Mechanistically, H2O2 primarily activates the MAPK pathways to induce viral lytic gene expression and replication. This new finding defines a novel role of H2O2 in KS tumorigenesis and highlights great potentials of using antioxidants and anti-inflammatory drugs for the prevention and treatment of KS tumors.

Open Access Article

Genotoxic stress-mediated cell cycle activities for the decision of cellular fate

Adnan Erol
Pages 3239 - 3248
http://dx.doi.org/10.4161/cc.10.19.17460
Abstract | PDF

Genomic integrity maintenance is critical for prevention of a wide variety of adverse cellular effects including apoptosis, cellular senescence, and malignant cell transformation. Coupled with normal replication, the local intracellular and extracellular stresses cause damage to cellular DNA that is recognized and repaired by the DNA damage response (DDR) pathway. p53 induces the transcription of genes that negatively regulate progression of the cell cycle in response to DNA damage, and thus participates in maintaining genome stability. p53 and many other anti-proliferative factors such as TGF beta regulate the expression of different cyclin-dependent kinase inhibitors (CDKIs). Paradoxically, one of the cellular proliferative factors, c-Myc proto-oncogene also controls the expression of these CDKIs and modulates the fate of cell in response to DNA damage. Furthermore, involvement of numerous other proteins in the DDR and crosstalk between them are likely to substantiate the DDR as one of the genome's most extensive signaling networks. Versatile protein kinases in this network affect the decision about four basic cellular fates, which are quiescence, apoptosis, oncogenesis and senescence, in response to DNA damage.




EXTRA VIEWS

Open Access Article

“Micromanaging” metabolic syndrome

Cristina M. Ramírez, Leigh Goedeke and Carlos Fernández-Hernando
Pages 3249 - 3252
http://dx.doi.org/10.4161/cc.10.19.17558
Abstract | PDF

Metabolic diseases are characterized by the failure of regulatory genes or enzymes to effectively orchestrate specific pathways involved in the control of many biological processes. In addition to the classical regulators of metabolic homeostasis, recent discoveries have shown the remarkable role of small non-coding RNAs (microRNAs) in the post-transcriptional regulation of a number of genes, and their involvement in many pathological states, such as diabetes, atherosclerosis and cancer. Of note is microRNA-33 (miR-33), an intronic microRNA (miRNA) located within the sterol regulatory element-binding protein (SREBP) genes, one of the master regulators of cholesterol and fatty acid metabolism. We have recently shown that miR-33 regulates cholesterol efflux and high-density lipoprotein (HDL) formation, as well as fatty acid oxidation and insulin signaling. These results describe a model in which miR-33 works in concert with its host genes to ensure that the cell’s metabolic state is balanced, thus highlighting the clinical potential of miRNAs as novel therapeutic targets for treating cardiometabolic diseases.

Open Access Article

TAp73 is downregulated in oocytes from women of advanced reproductive age

Maria Rosa Guglielmino, Manuela Santonocito, Marilena Vento, Marco Ragusa, Davide Barbagallo, Placido Borzì, Ida Casciano, Barbara Banelli, Ottavia Barbieri, Simonetta Astigiano, Paolo Scollo, Massimo Romani, Michele Purrello and Cinzia Di Pietro
Pages 3253 - 3256
http://dx.doi.org/10.4161/cc.10.19.17585
Abstract | PDF

Studies on oocyte transcriptome are important to understand the biological pathways involved in oogenesis, totipotence and early embryonic development. Moreover, genes regulating physiological pathways in gametes could represent potential candidates for reproductive disorders. In addition to oocyte specific transcription factors, also the members of the p53 family could be etiologically involved due to their biological functions. In fact, their role in the control of cell cycle, apoptosis, and germ-line genome stability is well known. Female reproductive aging is one of  the causes of fertility reduction and it is often associated with egg aneuploidy increase. In order to verify the potential involvement of p73 in reproductive aging, we determined its expression in single mature MII oocytes from two groups of women, younger than 35 or older than 38 years, respectively. We found that TAp73 isoforms are down regulated in oocytes from women older than 38 years. We confirmed these data in pools of mouse oocytes. TAp73 down regulation in oocytes from women of advanced reproductive age could explain both the reduction of fertility and the increase of newborns with chromosomal abnormalities.

Open Access Article

The ups and downs of p53 regulation in hematopoietic stem cells

Hussein A. Abbas, Vinod Pant and Guillermina Lozano
Pages 3257 - 3262
http://dx.doi.org/10.4161/cc.10.19.17721
Abstract | PDF

Hematopoietic stem cells provide an indispensible source for replenishing the blood with all its constituents throughout the organism's lifetime. Mice with a compromised hematopoietic stem cell compartment cannot survive. p53, a major tumor suppressor gene, has been implicated in regulation of hematopoiesis. In particular, p53 plays a role in homeostasis by regulating HSC quiescence and self renewal. We recently utilized a hypomorphic p53^515C allele in conjunction with Mdm2, a negative regulator of p53 to gain insights into the role of p53 in hematopoietic regulation. Our analyses revealed that p53^515C/515CMdm2^-/- double mutant mice die soon after birth due to hematopoietic failure. Further mechanistic studies revealed that in the absence of Mdm2, ROS induced postnatal p53 activity depletes hematopoietic stem cells, progenitors and differentiated cells.

Open Access Article

Oxidation of Akt2 kinase promotes cell migration and regulates G₁-S transition in the cell cycle

Revati Wani, N. Sharmila Bharathi, Jeffrey Field, Allen W. Tsang and Cristina M. Furdui
Pages 3263 - 3268
http://dx.doi.org/10.4161/cc.10.19.17738
Abstract | PDF

Phosphorylation has long been recognized as the key mediator of protein signaling. New modes of signaling regulation are emerging with the development of specific chemical probes and application of high-throughput mass spectrometry technologies. Using biotin-tagged chemical probes for protein oxidation, mass spectrometry and functional assays, our group has recently reported isoform-specific oxidation of Akt2 in response to PDGF signaling. The studies included here investigate the functional consequence of oxidation on Akt2-mediated cell migration and cell cycle. Akt2-KO MEFs transduced with WT and Cys124Ser Akt2 were used as the model system for these studies. The implications of these findings on disease pathology are discussed.

Open Access Article

FoxM1 knockdown sensitizes human cancer cells to proteasome inhibitor-induced apoptosis but not to autophagy

Bulbul Pandit and Andrei L. Gartel
Pages 3269 - 3273
http://dx.doi.org/10.4161/cc.10.19.17735
Abstract | PDF

Apoptosis has been widely accepted as the primary mechanism of drug-induced cell death. Recently, a second type of cell death pathway has been demonstrated: autophagy, also called programmed type II cell death. Autophagy is a highly regulated process, by which selected components of a cell are degraded. It primarily functions as a cell survival mechanism under stress. However, persistent stress can also promote extensive autophagy leading to cell death. Forkhead box M1 (FoxM1), an oncogenic transcription factor that is abundantly expressed in a wide range of human cancers. Here we evaluated the role of FoxM1 in sensitivity of human cancer cells to proteasome inhibitor-induced apoptosis and autophagy. We found that FoxM1 knockdown sensitized the human cancer cells to apoptotic cell death induced by proteasome inhibitors, such as, MG132, bortezomib and thiostrepton, while it did not affect the levels of autophagy following treatment with these drugs.




REVIEW

Open Access Article

Pleiotropic functions of EAPII/TTRAP/TDP2: Cancer development, chemoresistance and beyond

Chunyang Li, Shi-Yong Sun, Fadlo R. Khuri and Runzhao Li
Pages 3274 - 3283
http://dx.doi.org/10.4161/cc.10.19.17763
Abstract | PDF

EAPII (also called TTRAP, TDP2), a protein identified a decade ago, has recently been shown to function as an oncogenic factor. This protein was also proven to be the first 5’- tyrosyl-DNA phosphodiesterase. EAPII has been demonstrated to have promiscuous protein associations, broad responsiveness to various extracellular signals, and pleiotropic functions in the development of human diseases including cancer and neurodegenerative disease. Emerging data suggest that EAPII is a multi-functional protein: EAPII repairs enzyme (topoisomerase)-mediated DNA damage by removing phosphotyrosine from DNA adducts; EAPII is involved in multiple signal transduction pathways such as TNF-TNFR, TGFβ and MAPK, and EAPII is responsive to immune defense, inflammatory response, virus infection and DNA toxins (chemo or radiation therapy). This review focuses on the current understanding of EAPII biology and its potential relations to many aspects of cancer development, including chromosome instability, tumorigenesis, tumor metastasis and chemoresistance, suggesting it as a potential target for intervention in cancer and other human diseases.




REPORTS

Open Access Article

NIRF constitutes a nodal point in the cell cycle network and is a candidate tumor suppressor

Tsutomu Mori, Daisuke D. Ikeda, Toshihiko Fukushima, Seiichi Takenoshita and Hideo Kochi
Pages 3284 - 3299
http://dx.doi.org/10.4161/cc.10.19.17176
Abstract | PDF

In biological networks, a small number of "hub" proteins play critical roles in the network integrity and functions. The cell cycle network orchestrates versatile cellular functions through interactions between many signaling modules, whose defects impair diverse cellular processes, often leading to cancer. However, the network architecture and molecular basis that ensure proper coordination between distinct modules are unclear. Here, we show that the ubiquitin ligase NIRF (also known as UHRF2), which induces G1 arrest, interacts with multiple cell cycle proteins including cyclins (A2, B1, D1 and E1), p53 and pRB, and ubiquitinates cyclins D1 and E1. Consistent with its versatility, a bioinformatic network analysis demonstrated that NIRF is an intermodular hub protein that is responsible for the coordination of multiple network modules. Notably, intermodular hubs are frequently associated with oncogenesis. Indeed, we detected loss of heterozygosity of the NIRF gene in several kinds of tumors. When a cancer outlier profile analysis was applied to the Oncomine database, loss of the NIRF gene was found at statistically significant levels in diverse tumors. Importantly, a recurrent microdeletion targeting NIRF was observed in non-small cell lung carcinoma. Furthermore, NIRF is immediately adjacent to the single nucleotide polymorphism rs719725, which is reportedly associated with the risk of colorectal cancer. These observations suggest that NIRF occupies a prominent position within the cell cycle network, and is a strong candidate for a tumor suppressor whose aberration contributes to the pathogenesis of diverse malignancies.

Open Access Article

The Fanconi anemia pathway is downregulated upon macrophage differentiation through two distinct mechanisms

Wei-Ting Lu, Kimon Lemonidis, Ross M. Drayton and Thierry Nouspikel
Pages 3300 - 3310
http://dx.doi.org/10.4161/cc.10.19.17178
Abstract | PDF

The Fanconi anaemia (FA) pathway is a DNA-damage inducible pathway critical for genomic stability. FA patients typically display high cancer susceptibility and hypersensitivity to DNA-damaging agents such as cross-linkers and ionizing radiation. A key step in the activation of the FA pathway is monoubiquitination of the FancD2 protein. Here we report that the FA pathway is downregulated by two distinct mechanisms upon differentiation of THP-1 and HL-60 leukaemia cells into macrophages. Firstly, qRT-PCR analysis revealed a transcriptional downregulation of most components of the FA complex, including FancD2. Secondly, DNA damage-induced monoubiquitination of the remaining FancD2 became deficient at various stages of differentiation depending on the type of damage. This was attributed to the differentiation-induced downregulation of Chk1, which phosphorylates FancD2 as a prelude to its ubiquitination. Although Western blotting revealed that levels of FancD2 were greatly reduced in terminally differentiated macrophages and that FancD2 ubiquitination was abolished, double-strand breaks were proficiently repaired, likely through an increase in non-homologous end joining (NHEJ). It has been suggested that the FA pathway promotes repair of double-strand breaks via homologous recombination rather than NHEJ. Its downregulation in macrophages may thus be required to avoid promoting a repair mechanism that is inefficient in post-mitotic cells.

Open Access Article

Efficient induction of functional neurons from adult human fibroblasts

Ulrich Pfisterer, James Wood, Kristian Nihlberg, Oskar Hallgren, Leif Bjermer, Gunilla Westergren-Thorsson, Olle Lindvall and Malin Parmar
Pages 3311 - 3316
http://dx.doi.org/10.4161/cc.10.19.17584
Abstract | PDF

Cellular reprogramming is a rapidly developing technology by which somatic cells are turned into pluripotent stem cells or other somatic cell types through expression of specific combinations of genes. This allows for the generation of patient-specific cell lines that can serve as tools for understanding disease pathogenesis, for drug screens and, potentially, for cell replacement therapies. Several cellular models of neurological disorders based on induced pluripotent cells (iPS cells) have been developed, and iPS-derived neurons are being explored as candidates for transplantation. Recent findings show that neurons can also be induced directly from embryonic and postnatal somatic cells by expression of defined combinations of genes. This conversion does not occur through a pluripotent stem cell stage, which eliminates the risk for tumor formation. Here, we demonstrate for the first time that functional neurons can be generated via direct conversion of fibroblasts also from adult individuals. Thus, this technology is an attractive alternative to iPS cells for generating patient- and disease-specific neurons suitable for disease modeling and autologous transplantation.

Open Access Article

Jab1/CSN5 mediates E2F dependent expression of mitotic and apoptotic but not DNA replication targets

Huarui Lu, Xudong Liang, Olga A. Issaenko and Timothy C. Hallstrom
Pages 3317 - 3326
http://dx.doi.org/10.4161/cc.10.19.17618
Abstract | PDF

The E2F transcription factors are critical regulators of cell cycle and cell fate control. Several classes of E2F target genes have been categorized based on their roles in DNA replication, mitosis, apoptosis, DNA repair, etc. How E2Fs coordinate the appropriate and timely expression of these functionally disparate gene products is poorly understood at a molecular level. We previously showed that the E2F1 binding partner Jab1/CSN5 promotes E2F1-dependent induction of apoptosis but not proliferation. To better understand how Jab1 regulates E2F1 dependent transcription, we performed gene expression analysis to identify E2F target genes most and least affected by shRNA depletion of Jab1. We find that a significant number of apoptotic and mitotic E2F target genes are poorly expressed in cells lacking Jab1/CSN5, whereas DNA replication genes are generally still highly expressed. Chromatin immunoprecipitation analysis indicates that both Jab1 and E2F1 co-occupy apoptotic and mitotic, but not DNA replication target genes. We explored a potential connection between PI3K activity and Jab1/E2F1 target gene induction, and found that E2F1/Jab1 co-induction of apoptotic target genes can be inhibited by activated PI3K. Furthermore, PI3K activity interferes with formation of the E2F1/Jab1 complex by co-immunoprecipitation. Jab1/CSN5 is upregulated in a variety of human tumors, but it's unclear how its pro-proliferatory and apoptotic functions are regulated in this context. We explored the link between increased Jab1 levels and PI3K function in tumors and detected a highly significant correlation between elevated Jab1/CSN5 levels and PI3K activity in breast, ovarian, lung and prostate cancers.

Open Access Article

Global mitotic phosphorylation of C₂H₂ zinc finger protein linker peptides

Raed Rizkallah, Karen E. Alexander and Myra M. Hurt
Pages 3327 - 3336
http://dx.doi.org/10.4161/cc.10.19.17619
Abstract | PDF

Cessation of transcriptional activity is a hallmark of cell division. Many biochemical pathways have been shown and proposed over the past few decades to explain the silence of this phase. In particular, many individual transcription factors have been shown to be inactivated by phosphorylation. In this report, we show the simultaneous phosphorylation and mitotic redistribution of a whole class of modified transcription factors. C₂H₂ zinc finger proteins (ZFPs) represent the largest group of gene expression regulators in the human genome. Despite their diversity, C₂H₂ ZFPs display striking conservation of small linker peptides joining their adjacent zinc finger modules. These linkers are critical for DNA binding activity. It has been proposed that conserved phosphorylation of these linker peptides could be a common mechanism for the inactivation of the DNA binding activity of C₂H₂ ZFPs, during mitosis. Using a novel antibody, raised against the phosphorylated form of the most conserved linker peptide sequence, we are able to visualize the massive and simultaneous mitotic phosphorylation of hundreds of these proteins. We show that this wave of phosphorylation is tightly synchronized, starting in mid-prophase right after DNA condensation and before the breakdown of the nuclear envelope. This global phosphorylation is completely reversed in telophase. In addition, the exclusion of the phospho-linker signal from condensed DNA clearly demonstrates a common mechanism for the mitotic inactivation of C₂H₂ ZFPs.

Open Access Article

Role of caspase 9 in activation of HTLV-1 LTR expression by DNA damaging agents

Ammar Abou-Kandil, Rachel Chamias, Mahmoud Huleihel, W T. Godbey and Mordechai Aboud
Pages 3337 - 3345
http://dx.doi.org/10.4161/cc.10.19.17620
Abstract | PDF

Abstract Adult T-cell leukemia (ATL) is caused by HTLV-I. The viral Tax oncoprotein plays a central role in initiating the process to ATL. However, after infection HTLV-1 enters into latency, during which virus gene expression is very low, so that the level of Tax is likely insufficient for exerting its oncogenic activities. Therefore only 5% of the infected individuals may develop ATL several decades after infection. It is assumed that the transition from latency to ATL development requires at least a temporary activation of the latent virus in order to elevate Tax to its oncogenic threshold. We have previously found that DNA damaging agents, which usually induce apoptosis, can also activate the viral LTR and that the anti apoptosis Bcl-2 protein not only avoid their apoptosis induction but concomitantly prevents their LTR activation effect. Therefore, the present study was designed to identify the factor that while participating in the apoptotic cascade acts also to activate the viral LTR. For this purpose we employed ectopic vectors expressing these apoptotic factors together with potent shRNAs against each of them and anti caspase peptide inhibitors. We have found that in addition to its function as initiator of the mitochondrial apoptotic cascade, caspase 9 can acts also as an executer which among other non-apoptotic functions it forms an Sp1-p53 complex that activates the LTR by binding to an Sp1 recognition site residing in the LTR. This finding can help in designing effective preventing strategies against ATL development in clinically latent HTLV-1 carriers.

Open Access Article

Pharmacological activation of p53 triggers anticancer innate immune response through induction of ULBP2

Hai Li, Tadepally Lakshmikanth, Cinzia Garofalo, Martin Enge, Clemens Spinnler, Andrea Anichini, Laszlo Szekely, Klas Kärre , Ennio Carbone and Galina Selivanova
Pages 3346 - 3358
http://dx.doi.org/10.4161/cc.10.19.17630
Abstract | PDF

Escape of tumor cells from cell-intrinsic barrier mediated by tumor suppressors and cell-extrinsic barrier mediated by the immune system is crucial for tumorigenesis. Growing evidence suggests that reactivation of tumor suppressor function or restoration of anticancer immunity is promising strategy for anticancer therapy due to their high potential to combat cancer. p53, a key tumor suppressor, represses tumorigenesis by eliciting growth arrest, apoptosis or senescence in cancer cells. Here, we unravel that, apart from these cell-autonomous effects, p53 activates the innate immune response against cancer cells. Our results show that pharmacological reactivation of p53 can stimulate the expression of ULPB2, a ligand for NK cell activating receptor NKG2D in human tumor cells of different origin, which enhance the susceptibility of tumor cells to NK cell-mediated killing. The molecular mechanism controlling ULPB2 expression by p53 is neither ATM/ATR- nor caspase-dependent. Using several approaches, we identified p53 as a direct transcriptional regulator of ULBP2 and found a p53 response element within ULBP2 gene, which confers the p53 regulation. Furthermore, we demonstrated that demethylation of p53-binding region within ULBP2 gene was required for p53-dependent induction of ULPB2, which can be achieved via repression of DNA methyltransferases (DNMTs) by p53. This molecular evidence for the direct control of immunosurveillance by p53 links tumor suppressor activation to innate immune stimuli and provides a possibility to integrate cell-extrinsic and -intrinsic defenses against tumorigenesis by pharmacological activation of p53, which may increase the probability to achieve a durable therapeutic success.

Open Access Article

Salivary miRNAome profiling uncovers epithelial and proliferative miRNAs with differential expression across dentition stages

Amanda Formosa, Maria Cristina Piro, Raffaella Docimo, Paolo Maturo, Daniela Rita Maria Sollecito , Murugan Kalimutho, Giulia Sancesario, Alberto Barlattani , Gerry Melino, Eleonora Candi and Sergio Bernardini
Pages 3359 - 3368
http://dx.doi.org/10.4161/cc.10.19.17647
Abstract | PDF

Saliva's ability to mirror the internal physiological environment of an organism coupled with its facile accessibility makes it an attractive diagnostic medium. The finding of microRNAs (miRNAs) in saliva has expanded the field of biomarker discovery since these tiny non-coding RNAs affect various physiological processes and diseases. Few reports have linked miRNAs to tooth development and eruption, with none having studied this in humans. As a first initiative to describe miRNAs in saliva whose modulations may reflect developing and erupting teeth, we quantified the levels of 730 miRNAs in the saliva of children of varying dentition stages: edentulous (newborns), deciduous and permanent by megaplex stemloop reverse-transcription quantitative PCR. The three groups expressed 193, 181 and 192 miRNAs, respectively, where 125 miRNAs had consistent expression. The remaining miRNAs had inter-group variations from 5 to hundreds of fold, where most had either an increasing or decreasing trend in going from edentulous to deciduous to permanent. A literature survey of epithelial miRNAs found most were present in saliva. Moreover, many miRNAs with expression differences between groups had previously documented functions in proliferation, cell cycle, apoptosis and other cellular behaviours key to the dynamics of tooth morphogenesis. Lastly, miRNAs of the same family, such as the let-7 and miR-200 families, or transcribed from the same hairpin, had similar expression patterns. The results presented here should serve as a salivary miRNA dictionary for future studies in tooth development as well as in childhood diseases associated with modulations in saliva composition.

Open Access Article

The CENP-A chaperone Scm3 becomes enriched at kinetochores in anaphase independently of CENP-A incorporation

Lucia Luconi, Yasuhiro Araki, Sarah Erlemann and Elmar Schiebel
Pages 3369 - 3378
http://dx.doi.org/10.4161/cc.10.19.17663
Abstract | PDF

Centromeres are specialized chromatin domains where kinetochores assemble. Centromeres contain as a conserved feature nucleosomes that are composed of the canonical histones H2A, H2B and H4 and a centromere-specific histone H3 variant, known as CENP-A in humans and Cse4 in budding yeast. The incorporation of CENP-A homologues into centromeric chromatin is cell cycle regulated and is assisted by related assembly factors named Scm3 in yeast and HJURP in human cells. Here we describe that the budding yeast Scm3 binds weakly to centromeres during interphase including S phase when Cse4 assembles into centromeres. In anaphase Scm3 then becomes 2.5-fold enriched at kinetochores where it is dynamic with a half recovery time t1/2 of 36 s. In contrast, Cse4 is stably integrated into kinetochores. In addition, ten Scm3 molecules bind to a cluster of 16 kinetochores with 32 Cse4 molecules suggesting a 1:3 ratio at kinetochores between the two proteins. Analysis of conditional lethal scm3-1 mutant cells indicated that Scm3 participates in maintaining Cse4 at centromeres in anaphase. Thus, Scm3 interacts transiently with kinetochores in anaphase where it safeguards Cse4 even after its S phase incorporation into centromeres.

Open Access Article

Shh is required for Tabby hair follicle development

Chang-Yi Cui, Makoto Kunisada, Victoria Childress, Marc Michel and David Schlessinger
Pages 3379 - 3386
http://dx.doi.org/10.4161/cc.10.19.17669
Abstract | PDF

In embryonic Eda mutant ("Tabby") mice, the development of one of the two major types of hair, "primary" hair fails, but other "secondary" hairs develop in normal numbers, though shorter and slightly aberrant. In Tabby mice, Shh is undetectable in skin early on, but is activated during secondary hair formation. We inferred that Shh may be involved in primary hair formation, activated normally by Eda, and also possibly in secondary hair formation, activated by an Eda-independent pathway. Varying the dosage of Shh now supports these inferences. In Shh knockout mice, mice were totally hairless: primary and secondary hair follicle germs were formed, but further progression failed. Consistent with these findings, when Shh loss was restricted to the skin, secondary hair follicle germs were initiated on time in Tabby mice, but their subsequent development (down-growth) failed. An Shh transgene expressed in Tabby skin could not restore induction of primary hair follicles, but restored normal length to the somewhat aberrant secondary hair that was formed and prolonged the anagen phase of hair cycling. Thus, Shh is required for primary and secondary hair down-growth and full secondary hair length, but is not itself sufficient to replace Eda or make fully normal secondary hair.

Open Access Article

Mutations in the β-tubulin binding site for peloruside A confer resistance by targeting a cleft significant in side chain binding

Adrian Begaye, Shana Trostel, Zhiming Zhao, Richard E. Taylor, David C. Schriemer and Dan L. Sackett
Pages 3387 - 3396
http://dx.doi.org/10.4161/cc.10.19.17706
Abstract | PDF

Peloruside A is a microtubule-stabilizing macrolide that binds to beta tubulin at a site distinct from the taxol site. The site was previously identified by H-D exchange mapping and molecular docking as a region close to the outer surface of the microtubule and confined in a cavity surrounded by a continuous loop of protein folded so as to center on Y340. We have isolated a series of peloruside A-resistant lines of the human ovarian carcinoma cell line A2780(1A9) to better characterize this binding site and the consequences of altering residues in it. Four resistant lines (Pel A-D) are described with single-base mutations in class I β-tubulin that result in the following substitutions: R306H, Y340S, N337D, and A296S in various combinations. The mutations are localized to peptides previously identified by Hydrogen-Deuterium exchange mapping, and center on a cleft in which the drug side chain appears to dock. The Pel lines are 10-15-fold resistant to peloruside A and show cross resistance to laulimalide but not to any other microtubule stabilizers. They show no cross-sensitivity to any microtubule destabilizers, nor to two drugs with targets unrelated to microtubules. Peloruside A induces G2/M arrest in the Pel cell lines at concentrations 10-15 times that required in the parental line. The cells show notable changes in morphology compared to the parental line.

Open Access Article

Novel peptide binds EWS-FLI1 and reduces the oncogenic potential in Ewing tumors

Hayriye V. Erkizan, Lauren J. Scher, S. Ellen Gamble, Julie S. Barber-Rotenberg, Kamal P. Sajwan, Aykut Uren and Jeffrey A. Toretsky
Pages 3397 - 3408
http://dx.doi.org/10.4161/cc.10.19.17734
Abstract | PDF

Ewing tumor is driven by the oncogenic EWS-FLI1 fusion protein that functions as an aberrant transcription factor. The identification of EWS-FLI1 protein partners is essential to enhance its vulnerability as a therapeutic target. We utilized phage display library screening against recombinant EWS-FLI1 protein. We identified 27 unique Ewing sarcoma binding peptides. The cytotoxicity evaluation of these peptides with in EWS-FLI1 containing cell lines yielded one potent peptide called ESAP1 (TMRGKKKRTRAN). ESAP1 binds EWS-FLI1 with 0.202 micromolar affinity as measured in surface plasmon resonance. The minimal interaction region of ESAP1 is characterized and found that the lysine residues are critical for cellular cytotoxicity. ESAP1 reduces the transcriptional activity of EWS-FLI1 as well as disrupts cell cycle kinetics in Ewing Tumor cells. These findings provide both a novel experimental probe and a potential therapeutic scaffold for Ewing Tumor.