Table of Contents

Volume 11, Issue 9

  May 1, 2012

  Pages 1665 - 1861

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 Issue Catalogue (MARC XML)

Hypometabolism and the Cell Cycle

EDITORIAL

Open Access Article

Hypometabolism and the cell cycle

Kenneth B. Storey
Page 1665
http://dx.doi.org/10.4161/cc.19973
Full Text | PDF

REVIEWS

Open Access Article

Developmental decisions: Balancing genetics and the environment by C. elegans

David V. Tobin and Richard Mako Saito
Pages 1666 - 1671
http://dx.doi.org/10.4161/cc.19443
Abstract | Full Text | PDF

The small nematode C. elegans is characterized by developing through a highly coordinated, reproducible cell lineage that serves as the basis of many studies focusing on the development of multi-lineage organisms. Indeed, the reproducible cell lineage enables discovery of developmental defects that occur in even a single cell. Only recently has attention been focused on how these animals modify their genetically programmed cell lineages to adapt to altered environments. Here, we summarize the current understanding of how C. elegans responds to food deprivation by adapting their developmental program in order to conserve energy. In particular, we highlight the AMPK-mediated and insulin-like growth factor signaling pathways that are the principal regulators of induced cell cycle quiescence.

Open Access Article

Suspended animation, diapause and quiescence: Arresting the cell cycle in C. elegans

Pamela A. Padilla and Mary L. Ladage
Pages 1672 - 1679
http://dx.doi.org/10.4161/cc.19444
Abstract | Full Text | PDF

Developing organisms require nutrients to support cell division vital for growth and development. An adaptation to stress, used by many organisms, is to reversibly enter an arrested state by reducing energy-requiring processes, such as development and cell division. This “wait it out” approach to survive stress until the environment is conductive for growth and development is used by many metazoans. Much is known about the molecular regulation of cell division, metazoan development and responses to environmental stress. However, how these biological processes intersect is less understood. Here, we review studies conducted in Caenorhabditis elegans that investigate how stresses such as oxygen deprivation (hypoxia and anoxia), exogenous chemicals or starvation affect cellular processes in the embryo, larvae or adult germline. Using C. elegans to identify how stress signals biological arrest can help in our understanding of evolutionary pressures as well as human health-related issues.

Open Access Article

Staying alive: Metabolic adaptations to quiescence

James R. Valcourt, Johanna M.S. Lemons, Erin M. Haley, Mina Kojima, Olukunle O. Demuren and Hilary A. Coller
Pages 1680 - 1696
http://dx.doi.org/10.4161/cc.19879
Abstract | Full Text | PDF

Quiescence is a state of reversible cell cycle arrest that can grant protection against many environmental insults. In some systems, cellular quiescence is associated with a low metabolic state characterized by a decrease in glucose uptake and glycolysis, reduced translation rates and activation of autophagy as a means to provide nutrients for survival. For cells in multiple different quiescence model systems, including Saccharomyces cerevisiae, mammalian lymphocytes and hematopoietic stem cells, the PI3Kinase/TOR signaling pathway helps to integrate information about nutrient availability with cell growth rates. Quiescence signals often inactivate the TOR kinase, resulting in reduced cell growth and biosynthesis. However, quiescence is not always associated with reduced metabolism; it is also possible to achieve a state of cellular quiescence in which glucose uptake, glycolysis and flux through central carbon metabolism are not reduced. In this review, we compare and contrast the metabolic changes that occur with quiescence in different model systems.

Open Access Article

Cell cycle regulation during development and dormancy in embryos of the annual killifish Austrofundulus limnaeus

Jason E. Podrabsky and Kristin M. Culpepper
Pages 1697 - 1704
http://dx.doi.org/10.4161/cc.19881
Abstract | Full Text | PDF

Embryos of the annual killifish Austrofundulus limnaeus can enter into a state of metabolic dormancy, termed diapause, as a normal part of their development. In addition, these embryos can also survive for prolonged sojourns in the complete absence of oxygen. Dormant embryos support their metabolism using anaerobic metabolic pathways, regardless of oxygen availability. Dormancy in diapause is associated with high ATP and a positive cellular energy status, while anoxia causes a severe reduction in ATP content and large reductions in adenylate energy charge and ATP/ADP ratios. Most cells are arrested in the G₁/G₀ phase of the cell cycle during diapause and in response to oxygen deprivation. In this paper, we review what is known about the physiological and biochemical mechanisms that support metabolic dormancy in this species. We also highlight the great potential that this model holds for identifying novel therapies for human diseases such as heart attack, stroke and cancer.

REPORTS

Open Access Article

Evidence for cell cycle suppression and microRNA regulation of cyclin D1 during anoxia exposure in turtles

Kyle K. Biggar and Kenneth B. Storey
Pages 1705 - 1713
http://dx.doi.org/10.4161/cc.19790
Abstract | Full Text | PDF

The red-eared slider turtle (Trachemys scripta elegans) has a well-developed natural tolerance for oxygen deprivation that derives from biochemical adaptations, including anoxia-induced suppression of metabolic rate. We hypothesized that mechanisms that suppress ATP-expensive cell cycle activity would contribute significantly to establishing the hypometabolic state during anaerobiosis. Cyclin D1 is a critical regulator of the G₁ phase of the cell cycle and is regarded as key to initiating cell proliferation. The relative protein expression of cyclin D1 was analyzed in both whole-cell and nuclear fractions of liver, kidney and skeletal muscle from turtles exposed to 5 or 20 h of submergence anoxia. Expression of cyclin D1 in both total and nuclear fractions decreased significantly under anoxia in liver and kidney as compared with aerobic controls, but no significant change occurred in muscle. The relative phosphorylation state of cyclin D1 (threonine 286) was also unchanged during anoxia in all tissues. Since phosphorylation of threonine 286 is necessary for proteasomal degradation of cyclin D1, this implies that an alternative mechanism is responsible for cyclin D1 suppression in anoxia. Levels of cyclin D1 mRNA transcripts did not change under anoxia in any tissue, so a post-transcriptional method of regulation was implicated. Analysis of the 3’UTR of cyclin D1 showed the presence of both an AU-rich region and a conserved binding site for microRNA-16-1 and microRNA-15a. Levels of both microRNAs increased in liver and kidney (but not in muscle) under anoxic conditions, implicating microRNA inhibition of mRNA translation as the mechanism underlying the suppression of cyclin D1 protein levels in the anoxic turtle.

Open Access Article

Pattern of cellular quiescence over the hibernation cycle in liver of thirteen-lined ground squirrels

Cheng-Wei Wu and Kenneth B. Storey
Pages 1714 - 1726
http://dx.doi.org/10.4161/cc.19799
Abstract | Full Text | PDF

Mammalian hibernation is a state of seasonal heterothermy that consists of long periods of torpor at low body temperature interspersed with short periods of arousal back to euthermia. Entry into the hypometabolic state of torpor is achieved via a strong coordinated reduction of energy expenditures, particularly ATP-expensive activities, such as transcription and translation. The present study analyzes the status of the cell cycle during hibernation in liver of thirteen-lined ground squirrels (Ictidomys tridecemlineatus) and examines the expression levels of cell cycle regulators over six stages of the torpor-arousal cycle. Immunoblot analysis showed that the protein expression levels of cyclin D1 and cyclin E were reduced in liver (by 31% and 48%, respectively) during long-term torpor; however, during arousal from torpor, PCR analysis showed an upregulation of cyclin D1 transcript levels of about 1.5-fold. Protein expression of cyclin A and cyclin B1 were also elevated (1.57-fold and 2.44-fold, respectively) during early arousal from torpor, and in addition, cyclin A2 transcript levels increased by about 1.8-fold during arousal. Protein levels of two CKIs, p15^INK4b and p21^CIP1, each increased by about 1.4-fold during torpor, and transcript levels of p15^INK4b also rose by 1.7–2.1 fold during torpor, whereas p21^CIP1 transcripts increased by 1.5–1.7-fold. A reduction in cyclin D and E protein expression coupled with upregulation of p15^INK4b and p21^CIP1 inhibitors during torpor reflects markers of cell cycle arrest during hibernation. Elevated expression of cyclin A and B protein expression during arousal stages of torpor suggests cell cycle progression is reversibly arrested during torpor and is reinitiated upon return to euthermia.

Open Access Article

Cell cycle regulation in the freeze tolerant wood frog, Rana sylvatica

Jing Zhang and Kenneth B. Storey
Pages 1727 - 1742
http://dx.doi.org/10.4161/cc.19880
Abstract | Full Text | PDF

The wood frog (Rana sylvatica) is one of only a few vertebrate species that can survive extensive freezing of its body fluids during the winter. The mechanisms of natural freeze tolerance include metabolic rate depression to conserve energy and the implementation of cryoprotective strategies, especially the synthesis of huge amounts of glucose as a cryoprotectant. Liver is the main source of glucose production/export (and other cryoprotective actions) and plays a central role in freezing survival of the whole animal. Freezing is a multi-component stress that includes anoxia/ischemia due to the cessation of blood flow and dehydration of cells caused by ice accumulation in extracellular spaces. To help endure these stresses, cells need to suppress and reprioritize ATP-expensive cell functions. One of these is cell growth and proliferation, and we hypothesized that cell cycle arrest would be key to freezing survival. The present study examines the responses by key cell cycle components to freezing, anoxia and dehydration stresses in wood frog liver. Immunoblotting was used to investigate protein expression of Cdc 2, Cdks (2, 4, 6), and cyclins (A, B1, D1, E) as well as the phosphorylation states of Cdks (Thr14/Tyr15), the phosphatases Cdc25a (Ser76) and Cdc25c (Ser216) and the CIP/KIP Cdk inhibitors p21 (Thr145) and p27 (Thr187). Responses to 24 h freezing, 24 h anoxia and 40% dehydration as well as recovery from these stresses were analyzed. The results showed very similar responses by cell cycle components to anoxia or dehydration and were consistent with cell cycle suppression under stress and reversal during recovery. Freezing showed elements of cell cycle suppression, including reduced protein levels of Cdks and cyclins A and B1, but also showed unique responses by cyclin D1, Cdc25 phosphatases and p21/p27. These may be linked with alternative actions by these proteins that contribute to cryoprotection; e.g., an alternative action of cyclin D1 as a transcription factor may contribute to the upregulation of glucose-6-phosphatase, a key enzyme needed for the export of glucose cryoprotectant.




EDITORIALS: CELL CYCLE FEATURES

Open Access Article

Context-dependent dual and opposite roles of nemo-like kinase in the Wnt/β-catenin signaling

Tohru Ishitani
Pages 1743 - 1745
http://dx.doi.org/10.4161/cc.20183
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Open Access Article

Pro-apoptotic signaling pathway by CDK5 and MEKK1

Hyung Don Ryoo
Pages 1746 - 1747
http://dx.doi.org/10.4161/cc.20184
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Open Access Article

Monocytes, viruses and metaphors: Hanging the Trojan horse

Jonathan W. Yewdell and Christopher B. Brooke
Pages 1748 - 1749
http://dx.doi.org/10.4161/cc.20311
Full Text | PDF

Open Access Article

TORC1-mediated protein synthesis regulates cilia size and function: Implications for organelle size control by diverse signaling cascades

Shiaulou Yuan and Zhaoxia Sun
Pages 1750 - 1752
http://dx.doi.org/10.4161/cc.20312
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CELL CYCLE NEWS & VIEWS

Open Access Article

Tumor-stroma relationships: Who’s the driver?

Richard F. Wooster
Page 1753
http://dx.doi.org/10.4161/cc.20185
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Open Access Article

Peptidyl-prolyl isomerization for cytokinetic abscission: Fold and cut

Armando van der Horst and Kum Kum Khanna
Page 1754
http://dx.doi.org/10.4161/cc.20313
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Open Access Article

A new tool for an old problem: Synchronizing fission yeast cells during meiosis using an ATP analog-sensitive protein kinase

Jozef Nosek and Ľubomír Tomáska
Page 1755
http://dx.doi.org/10.4161/cc.20314
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Open Access Article

CHEKing out of mitosis

Aneliya Velkova and Alvaro N.A. Monteiro
Page 1756
http://dx.doi.org/10.4161/cc.20315
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EXTRA VIEWS

Open Access Article

From oncogene to tumor suppressor: The dual role of Myc in leukemia

Iris Uribesalgo, Salvador Aznar Benitah and Luciano Di Croce
Pages 1757 - 1764
http://dx.doi.org/10.4161/cc.19883
Abstract | Full Text | PDF

The transcription factor c-Myc strongly stimulates cell proliferation but also regulates apoptosis, senescence, cell competition and cell differentiation, and its elevated activity is a hallmark for human tumorigenesis. c-Myc induces transcription by forming heterodimers with Max and then directly binding DNA at E-box sequences. Conversely, transcription repression depends primarily on the inhibitory interaction of c-Myc/Max with Miz-1 at DNA initiator elements. We recently described a distinct mechanism of c-Myc gene regulation, in which c-Myc interacts with the retinoic acid receptor α (RARα) and is recruited to RAR DNA binding sequences (RAREs). In leukemia cells, this c-Myc/RARα complex functions either as an activator or a repressor of RARα-dependent targets through a phosphorylation switch. Unphosphorylated c-Myc interacts with RARα to repress the expression of RAR targets required for differentiation, thereby aggravating leukemia malignancy. However, if c-Myc is phosphorylated by the kinase Pak2, the c-Myc/RARα complex activates transcription of those same genes to stimulate differentiation, thus reducing tumor burden. Here, we discuss the role of c-Myc in balancing proliferation and differentiation and how modulating this previously unidentified c-Myc activity might provide alternative therapies against leukemia and possibly other types of tumors.




REVIEW

Open Access Article

Manzamines: A potential for novel cures

Mona Radwan, Amro Hanora, Sherief Khalifa and Soad H. Abou-El-Ela
Pages 1765 - 1772
http://dx.doi.org/10.4161/cc.20135
Abstract | Full Text | PDF

Manzamines are a unique class of β-carboline marine alkaloids with an unusual tetra- or pentacyclic system. These alkaloids have shown a variety of bioactivities against infectious diseases, cancer and inflammatory diseases. The greatest potential for the manzamine alkaloids appears to be against malaria, with improved potency relative to chloroquine and artemisinin. Over 80 manzamine-related alkaloids have been isolated from more than 16 species of marine sponges belonging to five families distributed from the Red Sea to Indonesia, which suggests a possible microbial origin for manzamine alkaloids. The current review summarizes marine literature, focusing on the biological activities of manzamines, the possible microbial origin of this class of compounds and the Red Sea as a possible source of manzamines from biosynthetic gene clusters of Red Sea microbes.




REPORTS

Open Access Article

Activation of multiple cancer pathways and tumor maintenance function of the 3q amplified oncogene FNDC3B

Chunlin Cai, Megha Rajaram, Xin Zhou, Qing Liu, John Marchica, Jinyu Li and R. Scott Powers
Pages 1773 - 1781
http://dx.doi.org/10.4161/cc.20121
Abstract | Full Text | PDF

FNDC3B was recently identified in an oncogenomic screen for amplified oncogenes in hepatocellular carcinoma. It is located at 3q26 and is amplified in over 20% of cancers, usually as part of a broad amplified region encompassing the entire 3q arm. Consistent with an oncogenic role in multiple cancer types, we show here that overexpression of FNDC3B is capable of malignantly transforming mammary and kidney epithelial cells in addition to hepatocytes. To explore how FNDC3B transforms cells, we determined the cellular localization of its gene product and the cancer pathways that it activates. We found that the FNDC3B oncoprotein localizes to the Golgi network, and that its correct localization is essential for its transforming function. We found that overexpression of FNDC3B induces the epithelial-to-mesenchymal transition (EMT) and activates several cancer pathways, including PI3-kinase/Akt, Rb1 and TGFβ signaling. For TGFβ signaling, we analyzed the point in the pathway at which FNDC3B operates and obtained evidence that it induces expression of all three TGFβ ligands and also promotes TGFBR1 cell-surface localization. We found that RNAi-mediated knockdown of FNDC3B in cancer cells with 3q amplification suppressed their clonogenicity and tumorigenicity, but that the same RNAi knockdown had no effect on single-copy 3q cancer cells. These results indicate that FNDC3B is an important oncogenic driver gene of the 3q amplicon, adding to the growing list of oncogenic drivers within this commonly amplified region.

Open Access Article

Delayed cell cycle pathway modulation facilitates recovery after spinal cord injury

Junfang Wu, Bogdan A. Stoica, Michael Dinizo, Ahdeah Pajoohesh-Ganji, Chunshu Piao and Alan I. Faden
Pages 1782 - 1795
http://dx.doi.org/10.4161/cc.20153
Abstract | Full Text | PDF

Traumatic spinal cord injury (SCI) causes tissue loss and associated neurological dysfunction through mechanical damage and secondary biochemical and physiological responses. We have previously described the pathobiological role of cell cycle pathways following rat contusion SCI by examining the effects of early intrathecal cell cycle inhibitor treatment initiation or gene knockout on secondary injury. Here, we delineate changes in cell cycle pathway activation following SCI and examine the effects of delayed (24 h) systemic administration of flavopiridol, an inhibitor of major cyclin-dependent kinases (CDKs), on functional recovery and histopathology in a rat SCI contusion model. Immunoblot analysis demonstrated a marked upregulation of cell cycle-related proteins, including pRb, cyclin D1, CDK4, E2F1 and PCNA, at various time points following SCI, along with downregulation of the endogenous CDK inhibitor p27. Treatment with flavopiridol reduced induction of cell cycle proteins and increased p27 expression in the injured spinal cord. Functional recovery was significantly improved after SCI from day 7 through day 28. Treatment significantly reduced lesion volume and the number of Iba-1⁺ microglia in the preserved tissue and increased the myelinated area of spared white matter as well as the number of CC1⁺ oligodendrocytes. Furthermore, flavopiridol attenuated expression of Iba-1 and glactin-3, associated with microglial activation and astrocytic reactivity by reduction of GFAP, NG2, and CHL1 expression. Our current study supports the role of cell cycle activation in the pathophysiology of SCI and by using a clinically relevant treatment model, provides further support for the therapeutic potential of cell cycle inhibitors in the treatment of human SCI.

Open Access Article

ATM-dependent phosphorylation of the checkpoint clamp regulates repair pathways and maintains genomic stability

Min Hwa Shin, Ming Yuan, Hao Zhang, Joseph B. Margolick and Mihoko Kai
Pages 1796 - 1803
http://dx.doi.org/10.4161/cc.20161
Abstract | Full Text | PDF

Upon genotoxic stress and during normal S phase, ATM phosphorylates the checkpoint clamp protein Rad9 in a manner that depends on Ser272. Ser272 is the only known ATM-dependent phosphorylation site in human Rad9. However, Ser272 phosphorylation is not required for survival or checkpoint activation after DNA damage. The physiological function of Ser272 remains elusive. Here, we show that ATM-dependent Rad9^Ser272 phosphorylation requires the MRN complex and controls repair pathways. Furthermore, the mutant cells accumulate large numbers of chromosome breaks and induce gross chromosomal rearrangements. Our findings establish a new and unexpected role for ATM: it phosphorylates the checkpoint clamp in order to control repair pathways, thereby maintaining genomic integrity during unperturbed cell cycle and upon DNA damage.

Open Access Article

Chalcone-based small-molecule inhibitors attenuate malignant phenotype via targeting deubiquitinating enzymes

Olga A. Issaenko and Alexander Yu Amerik
Pages 1804 - 1817
http://dx.doi.org/10.4161/cc.20174
Abstract | Full Text | PDF

The ubiquitin-proteasome system (UPS) is usurped by many if not all cancers to regulate their survival, proliferation, invasion, angiogenesis and metastasis. Bioflavonoids curcumin and chalcones exhibit anti-neoplastic selectivity through inhibition of the 26S proteasome-activity within the UPS. Here, we provide evidence for a novel mechanism of action of chalcone-based derivatives AM146, RA-9 and RA-14, which exert anticancer activity by targeting deubiquitinating enzymes (DUB) without affecting 20S proteasome catalytic-core activity. The presence of the α,β-unsaturated carbonyl group susceptible to nucleophilic attack from the sulfhydryl of cysteines in the active sites of DUB determines the capacity of novel small-molecules to act as cell-permeable, partly selective DUB inhibitors and induce rapid accumulation of polyubiquitinated proteins and deplete the pool of free ubiquitin. These chalcone derivatives directly suppress activity of DUB UCH-L1, UCH-L3, USP2, USP5 and USP8, which are known to regulate the turnover and stability of key regulators of cell survival and proliferation. Inhibition of DUB-activity mediated by these compounds downregulates cell cycle promoters, e.g., cyclin D1 and upregulates tumor suppressors p53, p27Kip1 and p16Ink4A. These changes are associated with arrest in S-G2/M, abrogated anchorage-dependent growth and onset of apoptosis in breast, ovarian and cervical cancer cells without noticeable alterations in primary human cells. Altogether, this work provides evidence of antitumor activity of novel chalcone-based derivatives mediated by their DUB-targeting capacity; supports the development of pharmaceuticals to directly target DUB as a most efficient strategy compared with proteasome inhibition and also provides a clear rationale for the clinical evaluation of these novel small-molecule DUB inhibitors.

Note: Please see the Expression of Concern published regarding this Report.

Open Access Article

Decreased translation of p21^waf1 mRNA causes attenuated p53 signaling in some p53 wild-type tumors

Li-Ju Chang and Alan Eastman
Pages 1818 - 1826
http://dx.doi.org/10.4161/cc.20208
Abstract | Full Text | PDF

DNA damage induces cell cycle arrest through both Chk1 and the p53 tumor suppressor protein, the latter arresting cells through induction of p21^waf1 protein. Arrest permits cells to repair the damage and recover. The frequent loss of p53 in tumor cells makes them more dependent on Chk1 for arrest and survival. However, some p53 wild type tumor cell lines, such as HCT116 and U2OS, are also sensitive to inhibition of Chk1 due to attenuated p21^waf1 induction upon DNA damage. The purpose of this study is to determine the cause of this attenuated p21^waf1 protein induction. We find that neither the induction of p21^waf1 mRNA nor protein half-life is sufficient to explain the low p21^waf1 protein levels in HCT116 and U2OS cells. The induced mRNA associates with polysomes but little protein is made suggesting these two cell lines have a reduced rate of p21^waf1 mRNA translation. This represents a novel mechanism for disruption of the p53-p21^waf1 pathway as currently known mechanisms involve either mutation of p53 or reduction of p53 protein levels. As a consequence, this attenuated p21^waf1 expression may render some p53 wild type tumors sensitive to a combination of DNA damage plus checkpoint inhibition.

Open Access Article

Phosphoproteomic analysis of cells treated with longevity-related autophagy inducers

Martin V. Bennetzen, Guillermo Mariño, Dennis Pultz, Eugenia Morselli, Nils J. Færgeman, Guido Kroemer and Jens S. Andersen
Pages 1827 - 1840
http://dx.doi.org/10.4161/cc.20233
Abstract | Full Text | PDF

Macroautophagy is a self-cannibalistic process that enables cells to adapt to various stresses and maintain energy homeostasis. Additionally, autophagy is an important route for turnover of misfolded proteins and damaged organelles, with important implications in cancer, neurodegenerative diseases and aging. Resveratrol and spermidine are able to induce autophagy by affecting deacetylases and acetylases, respectively, and have been found to extend the life-span of model organisms. With the aim to reveal the signaling networks involved in this drug-induced autophagic response, we quantified resveratrol and spermidine-induced changes in the phosphoproteome using SILAC and mass spectrometry. The data were subsequently analyzed using the NetworKIN algorithm to extract key features of the autophagy-responsive kinase-substrate network. We found that two distinct sequence motifs were highly responsive to resveratrol and spermidine and that key proteins modulating the acetylation, phosphorylation, methylation and ubiquitination status were affected by changes in phosphorylation during the autophagic response. Essential parts of the apoptotic signaling network were subjected to post-translational modifications during the drug-induced autophagy response, suggesting potential crosstalk and balancing between autophagy and apoptosis. Additionally, we predicted cellular signaling networks affected by resveratrol and spermidine using a computational framework. Altogether, these results point to a profound crosstalk between distinct networks of post-translational modifications and provide a resource for future analysis of autophagy and cell death.

Open Access Article

Integrating role of T antigen, Rb2/p130, CTCF and BORIS in mediating non-canonical endoplasmic reticulum-dependent death pathways triggered by chronic ER stress in mouse medulloblastoma

Marcella Macaluso, Valentina Caracciolo, Valeria Rizzo, Ang Sun, Micaela Montanari, Giuseppe Russo, Gianfranco Bellipanni, Kamel Khalili and Antonio Giordano
Pages 1841 - 1850
http://dx.doi.org/10.4161/cc.20242
Abstract | Full Text | PDF

Distinct molecular pathways could be constitutively active in mouse T-Antigen positive and T-Antigen negative medulloblastoma cell lines, contributing to their phenotypic differences as well as to cellular responses, cell cycle progression, cell death and survival. The diversity of these responses may be due, at least in part, to distinct activities of Rb2/p130, CTCF and BORIS proteins in response to an altered network of signaling evoked by the T-Ag presence. Here, we provided evidence supporting a role for the T-Antigen in causing chronic endoplasmic reticulum (ER) stress and aberrant Caspase-12 expression and activation, subsequently driving to both massive cell death, and perhaps selection of cells with a higher malignant phenotype. Furthermore, we observed that the endoplasmic stress, either chronically caused by T-Ag or transiently induced by glucose deprivation, is accompanied by the formation of complexes between the retinoblastoma related protein Rb2/p130 and the chromatin insulator CCCTC-binding factor CTCF, or the CTCF-paralogue BORIS. Our study represents the first evidence supporting a role of the T-Antigen in inducing/maintaining chronic ER-stress, as well as, indicating a role of Rb2/p130, CTCF and BORIS as potential mediators of non-canonical ER-dependent death pathway in mouse medulloblastoma.

Open Access Article

An evaluation of small-molecule p53 activators as chemoprotectants ameliorating adverse effects of anticancer drugs in normal cells

Ingeborg M.M. van Leeuwen, Bhavya Rao, Marijke C.C. Sachweh and Sonia Lain
Pages 1851 - 1861
http://dx.doi.org/10.4161/cc.20254
Abstract | Full Text | PDF

Pharmacological activation of wild-type p53 has been found to protect normal cells in culture from cytotoxicity and nuclear aberrations caused by conventional cancer therapeutics. Hence, small-molecule p53 activators could have clinical benefits as chemoprotectants for cancer patients bearing p53-mutant tumors. We have evaluated 16 p53-based cyclotherapy regimes combining p53 activators tenovin-6, leptomycin B, nutlin-3 and low dose actinomycin D, with clinically utilized chemotherapeutic agents (S- and M-phase poisons), vinblastine, vinorelbine, cytosine arabinoside and gemcitabine. All the p53 activators induce reversible cell-cycle arrest in primary human fibroblasts and protect them from both S- and M-phase poisons. Furthermore, studies with p53-mutant cancer cell lines show that nutlin-3 and low dose actinomycin D do not affect the sensitivity of these cells to any of the chemotherapeutics tested. Thus, these two small molecules could be suitable choices for cyclotherapy regimes involving S- or M-phase poisons. In contrast, pre-incubation of p53-mutant cells with tenovin-6 or leptomycin B reduces the efficacy of vinca alkaloids, suggesting that these p53 activators could be effective as chemoprotectants if combined with S- but not M-phase poisons. Discrepancies were observed between the levels of protection detected immediately after treatment and following recovery in fresh medium. This highlights the need to assess both short- and long-term effects when evaluating compounds as potential chemoprotectants for cancer therapy.