Table of Contents

Volume 10, Issue 18

  September 15, 2011

  Pages 3031 - 3209

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 Issue Catalogue (MARC XML)

SPECIAL FEATURE

Open Access Article

CEE-ing is believing: Bioscience ventures in Central and Eastern Europe

Katrina Lamb
Pages 3031 - 3035
http://dx.doi.org/10.4161/cc.10.18.17559
Abstract | PDF

Bioscience ventures in Central and Eastern Europe are becoming a presence in world healthcare markets despite a perennially short supply of venture funding and other support mechanisms relative to other world economic regions. Here are three up-and-coming CEE stories worth keeping an eye on.




EDITORIALS: CELL CYCLE FEATURES

Open Access Article

p53 and epithelial-mesenchymal transition: A linking thread between embryogenesis and cancer

Rachel Sarig and Eldad Tzahor
Pages 3036 - 3037
http://dx.doi.org/10.4161/cc.10.18.16944
Abstract | PDF

Comment on: Rinon A, et al. Development 2011; 138:1827-38.

Open Access Article

Pathogenic DNA: Cytosolic DNA promotes inflammation in psoriasis

Jürgen Schauber, Yvonne Dombrowski and Robert Besch
Pages 3038 - 3039
http://dx.doi.org/10.4161/cc.10.18.16945
Abstract | PDF

Comment on: Dombrowski Y, et al. Sci Transl Med 2011; 3:82ra38.

Open Access Article

Nuclear actin in transcriptional reprogramming by oocytes: Are actin nucleators key players?

Kei Miyamoto, Vincent Pasque and John B. Gurdon
Pages 3040 - 3041
http://dx.doi.org/10.4161/cc.10.18.16946
Abstract | PDF

Comment on: Miyamoto K, et al. Genes Dev 2011; 25:946-58.

Open Access Article

In search of housekeeping pathways that regulate longevity

Adam Beach and Vladimir I. Titorenko
Pages 3042 - 3044
http://dx.doi.org/10.4161/cc.10.18.16947
Abstract | PDF

Comment on: Goldberg AA, et al. Aging 2010; 2:393-414.

Open Access Article

Acetyl-CoA drives the transcriptional growth program in yeast

Ling Cai and Benjamin P. Tu
Pages 3045 - 3046
http://dx.doi.org/10.4161/cc.10.18.17000
Abstract | PDF

Comment on: Cai L, et al. Mol Cell 2011; 42:426-37.




CELL CYCLE NEWS & VIEWS

Open Access Article

Complexity of IFNγ signaling gets another twist

Andrey Sorokin
Page 3047
http://dx.doi.org/10.4161/cc.10.18.16765
Abstract | PDF

Comment on: Burova EB, et al. Cell Cycle 2011; 10:2197-205.

Open Access Article

What's going on at stalled forks?

William K. Kaufmann
Page 3048
http://dx.doi.org/10.4161/cc.10.18.16993
Abstract | PDF

Comment on: Trego KS, et al. Cell Cycle 2011; 10:1998-2007.

Open Access Article

SIRT1, p53 and mitotic chromosomes

Jo Milner and Simon J. Allison
Page 3049
http://dx.doi.org/10.4161/cc.10.18.16994
Abstract | PDF

Comment on: Fatoba ST, et al. Cell Cycle 2011; 10:2317-22.

Open Access Article

News on hypomethylating agents: Chasing the FOX

Kai Uwe Chow
Page 3050
http://dx.doi.org/10.4161/cc.10.18.16995
Abstract | PDF

Comment on: Thépot S, et al. Cell Cycle 2011; 10:2323-30.

Open Access Article

XPG and WRN: An unexpected partnership

Ashwini S. Kamath-Loeb and Lawrence A. Loeb
Page 3051
http://dx.doi.org/10.4161/cc.10.18.16996
Abstract | PDF

Comment on: Trego KS, et al. Cell Cycle 2011; 10:1998-2007.

Open Access Article

The "suppressive side" of yeast mitotic cyclins

Uttam Surana and Hong Hwa Lim
Page 3052
http://dx.doi.org/10.4161/cc.10.18.16997
Abstract | PDF

Comment on: Signon L. Cell Cycle 2011; 10:1655-68.

Open Access Article

Novel findings on actin regulation in asymmetric division of mouse oocytes

Heide Schatten
Page 3053
http://dx.doi.org/10.4161/cc.10.18.16998
Abstract | PDF

Comment on: Sun SC, et al. Cell Cycle 2011; 10:1853-60.

Open Access Article

Braking with 30 fingers: ZNF521 holds on Ebf1-dependent B-cell development

Riku Kiviranta and Roland Baron
Page 3054
http://dx.doi.org/10.4161/cc.10.18.16999
Abstract | PDF

Comment on: Mega T, et al. Cell Cycle 2011; 10:1853-60.

Open Access Article

An Aurora A-Lats-Aurora B axis ensures proper chromosome segregation

Noa Furth and Moshe Oren
Page 3055
http://dx.doi.org/10.4161/cc.10.18.17046
Abstract | PDF

Comment on: Yabuta N, et al. Cell Cycle 2011; 10: 2724-36.

Open Access Article

Defining bad stroma in human breast tumors

Anthony Howell
Page 3056
http://dx.doi.org/10.4161/cc.10.18.17047
Abstract | PDF

Comment on: Witkiewicz AK, et al. Cell Cycle 2011; 10:1794-809.




EXTRA VIEWS

Open Access Article

Roles of COP9 signalosome in cancer

Mong-Hong Lee, Ruiying Zhao, Liem Phan and Sai-Ching J. Yeung
Pages 3057 - 3066
http://dx.doi.org/10.4161/cc.10.18.17320
Abstract | PDF

The constitutive photomorphogenesis 9 signalosome (COP9 or CSN) is an evolutionarily conserved multiprotein complex found in plants and animals. Because of the homology between the COP9 signalosome and the 19S lid complex of the proteosome, COP9 has been postulated to play a role in regulating the degradation of polyubiquitinated proteins. Many tumor suppressor and oncogene products are regulated by ubiquitination- and proteosome-mediated protein degradation. Therefore, it is conceivable that COP9 plays a significant role in cancer, regulating processes relevant to carcinogenesis and cancer progression (e.g., cell cycle control, signal transduction and apoptosis). In mammalian cells, it consists of eight subunits (CSN1 to CSN8). The relevance and importance of some subunits of COP9 to cancer are emerging. However, the mechanistic regulation of each subunit in cancer remains unclear. Among the CSN subunits, CSN5 and CSN6 are the only two that each contain an MPN (Mpr1p and Pad1p N-terminal) domain. The deneddylation activity of an MPN domain toward cullin-RING ubiquitin ligases (CRL) may coordinate CRL-mediated ubiquitination activity. More recent evidence shows that CSN5 and CSN6 are implicated in ubiquitin-mediated proteolysis of important mediators in carcinogenesis and cancer progression. Here, we discuss the mechanisms by which some CSN subunits are involved in cancer to provide a much needed perspective regarding COP9 in cancer research, hoping that these insights will lay the groundwork for cancer intervention.

Open Access Article

Terminating protein ubiquitination: Hasta la vista, ubiquitin

Daniel K. Stringer and Robert C. Piper
Pages 3067 - 3071
http://dx.doi.org/10.4161/cc.10.18.17191
Abstract | PDF

Ubiquitination is a post-translational modification that generally directs proteins for degradation by the proteasome or by lysosomes. However, ubiquitination has been implicated in many other cellular processes, including transcriptional regulation, DNA repair, regulation of protein-protein interactions and association with ubiquitin-binding scaffolds. Ubiquitination is a dynamic process. Ubiquitin is added to proteins by E3 ubiquitin ligases as a covalent modification to one or multiple lysine residues as well as non-lysine amino acids. Ubiquitin itself contains seven lysines, each of which can also be ubiquitinated, leading to polyubiquitin chains that are best characterized for linkages occurring through K48 and K63. Ubiquitination can also be reversed by the action of deubiquitination enzymes (DUbs). Like E3 ligases, DUbs play diverse and critical roles in cells.¹ Ubiquitin is expressed as a fusion protein, as a linear repeat or as a fusion to ribosomal subunits, and DUbs are necessary to liberate free ubiquitin, making them the first enzyme of the ubiquitin cascade. Proteins destined for degradation by the proteasome or by lysosomes are deubiquitinated prior to their degradation, which allows ubiquitin to be recycled by the cell, contributing to the steady-state pool of free ubiquitin. Proteins destined for degradation by lysosomes are also acted upon by both ligases and DUbs. Deubiquitination can also act as a means to prevent protein degradation, and many proteins are thought to undergo rounds of ubiquitination and deubiquitination, ultimately resulting in either the degradation or stabilization of those proteins. Despite years of study, examining the effects of the ubiquitination of proteins remains quite challenging. This is because the methods that are currently being employed to study ubiquitination are limiting. Here, we briefly examine current strategies to study the effects of ubiquitination and describe an additional novel approach that we have developed.

Open Access Article

A GSK-3-mediated transcriptional network maintains repression of immediate early genes in quiescent cells

John W. Tullai, Julie R. Graham and Geoffrey M. Cooper
Pages 3072 - 3077
http://dx.doi.org/10.4161/cc.10.18.17321
Abstract | PDF

Glycogen synthase kinase-3 (GSK-3) plays a central role in cell survival and proliferation, in part by the regulation of transcription. Unlike most protein kinases, GSK-3 is active in quiescent cells in the absence of growth factor signaling. In a recent series of studies, we employed a systems-level approach to understanding the transcription network regulated by GSK-3 in a quiescent cell model. We identified a group of immediate early genes that were upregulated in quiescent cells solely by the inhibition of GSK-3 in the absence of growth factor stimulation. Computational analysis of the upstream sequences of these genes identified statistically over-represented binding sites for the transcription factors CREB, NFκB and AP-1, and the roles of these factors in regulating expression of GSK-3 target genes were verified by chromatin immunoprecipitation and RNA interference. In quiescent cells, GSK-3 inhibits CREB, NFκB and AP-1, thereby maintaining repression of their target genes and contributing to maintenance of cell cycle arrest.

Open Access Article

Processing of homologous recombination repair intermediates by the Sgs1-Top3-Rmi1 and Mus81-Mms4 complexes

Ian D. Hickson and Hocine W. Mankouri
Pages 3078 - 3085
http://dx.doi.org/10.4161/cc.10.18.16919
Abstract | PDF

Homologous recombination repair (HRR) is an evolutionarily conserved cellular process that is important for the maintenance of genome stability during S phase. Inactivation of the Saccharomyces cerevisiae Sgs1-Top3-Rmi1 complex leads to the accumulation of unprocessed, X-shaped HRR intermediates (X structures) following replicative stress. Further characterization of these X structures may reveal why loss of BLM (the human Sgs1 ortholog) leads to the human cancer predisposition disorder, Bloom syndrome. In two recent complementary studies, we examined the nature of the X structures arising in yeast strains lacking Sgs1, Top3 or Rmi1 by identifying which proteins could process these structures in vivo. We revealed that the unprocessed X structures that accumulate in these strains could be resolved by the ectopic overexpression of two different Holliday junction (HJ) resolvases, and that the endogenous Mus81-Mms4 endonuclease could also remove them, albeit slowly. In this review, we discuss the implications of these results and review the putative roles for the Sgs1-Top3-Rmi1 and Mus81-Mms4 complexes in the processing of various types of HRR intermediates during S phase.

Open Access Article

Network calisthenics: Control of E2F dynamics in cell cycle entry

Jeffrey V. Wong, Peng Dong, Joseph R. Nevins, Bernard Mathey-Prevot and Lingchong You
Pages 3086 - 3094
http://dx.doi.org/10.4161/cc.10.18.17350
Abstract | PDF

Stimulation of quiescent mammalian cells with mitogens induces an abrupt increase in E2F1–3 expression just prior to the onset of DNA synthesis, followed by a rapid decline as replication ceases. This temporal adaptation in E2F facilitates a transient pattern of gene expression that reflects the ordered nature of DNA replication. The challenge to understand how E2F dynamics coordinate molecular events required for high-fidelity DNA replication has great biological implications. Indeed, precocious, prolonged, elevated or reduced accumulation of E2F can generate replication stress that culminates in either arrest or death. Accordingly, temporal characteristics of E2F are regulated by several network modules that include feedforward and autoregulatory loops. In this review, we discuss how these network modules contribute to “shaping” E2F dynamics in the context of mammalian cell cycle entry.

Open Access Article

Linear polyubiquitin chains: A new modifier involved in NFκB activation and chronic inflammation, including dermatitis

Kazuhiro Iwai
Pages 3095 - 3104
http://dx.doi.org/10.4161/cc.10.18.17437
Abstract | PDF

The ubiquitin conjugation system regulates a wide variety of biological phenomena, including protein degradation and signal transduction, by regulating protein function via polyubiquitin conjugation in most cases. Several types of polyubiquitin chains exist in cells, and the type of polyubiquitin chain conjugated to a protein seems to determine how that protein is regulated. We identified a novel linear polyubiquitin chain and the ubiquitin-protein ligase complex that assembles it, designated LUBAC. Both were shown to have crucial roles in the canonical NFκB activation pathway. This year, three groups, including our laboratory, identified SHARPIN as a new subunit of LUBAC. Of great interest, Sharpin was identified as a causative gene of chronic proliferative dermatitis in mice (cpdm), which is characterized by numerous inflammatory symptoms including chronic dermatitis, arthritis and immune disorders. Deletion of SHARPIN drastically reduces the amount of LUBAC and attenuates signal-induced NFκB activation. The pleomorphic symptoms of cpdm mice suggest that LUBAC-mediated NFκB activation may play critical roles in mammals and be involved in various disorders. A forward look into the linear polyubiquitin research is also discussed.




REPORTS

Open Access Article

Unopposed mitochondrial fission leads to severe lifespan shortening

Christian Q. Scheckhuber, Ruth A. Wanger, Cora A. Mignat and Heinz D. Osiewacz
Pages 3105 - 3110
http://dx.doi.org/10.4161/cc.10.18.17196
Abstract | PDF

Mitochondrial morphology is controlled by the opposing processes of fusion and fission. Previously, in baker’s yeast it was shown that reduced mitochondrial fission leads to a network-like morphology, decreased sensitivity for the induction of apoptosis and a remarkable extension of both replicative and chronological lifespan. However, the effects of reduced mitochondrial fusion on aging are so far unknown and complicated by the fact that deletion of genes encoding components of mitochondrial fusion are often lethal to higher organisms. This is also true for the mammalian OPA1 protein, which is a key regulator of mitochondrial inner membrane fusion. Baker’s yeast contains an OPA1 ortholog, Mgm1p. Deletion of Mgm1 is possible in yeast due to the fact that mitochondrial function is not essential for growth on glucose-containing media. In this study, we report that absence of mitochondrial fusion in the Δmgm1 mutant leads to a striking reduction of both replicative and chronological lifespan. Concomitantly, sensitivity to apoptosis elicitation via the reactive oxygen species hydrogen peroxide is substantially increased. These results demonstrate that the unopposed mitochondrial fission as displayed by the Δmgm1 mutant strongly affects organismal aging. Moreover, our results bear important clues for translational research to intervene into age-related degenerative processes also in multicellular organisms including humans.

Open Access Article

ΔNp63α promotes cellular quiescence via induction and activation of Notch3

Sierra Kent, Justine Hutchinson, Amanda Balboni, Andrew DeCastro, Pratima Cherukuri and James DiRenzo
Pages 3111 - 3118
http://dx.doi.org/10.4161/cc.10.18.17300
Abstract | PDF

Genetic analysis of TP63 indicates that ΔNp63 isoforms are required for preservation of self-renewing capacity in the stem cell compartments of diverse epithelial structures; however, the underlying cellular and molecular mechanisms remain incompletely defined. Cellular quiescence is a common feature of adult stem cells that may account for their ability to retain long-term replicative capacity while simultaneously limiting cellular division. Similarly, quiescence within tumor stem cell populations may represent a mechanism by which these populations evade cytotoxic therapy and initiate tumor recurrence. Here, we present evidence that ΔNp63α, the predominant TP63 isoform in the regenerative compartment of diverse epithelial structuresm, promotes cellular quiescence via activation of Notch signaling. In HC11 cells, ectopic ΔNp63α mediates a proliferative arrest in the 2N state coincident with reduced RNA synthesis characteristic of cellular quiescence. Additionally, ΔNp63α and other quiescence-inducing stimuli enhanced expression of Notch3 in HC11s and breast cancer cell lines, and ectopic expression of the Notch3 intracellular domain (N3^ICD) was sufficient to cause accumulation in G₀/G₁ and increased expression of two genes associated with quiescence, Hes1 and Mxi1. Pharmacologic inhibition of Notch signaling or shRNA-mediated suppression of Notch3 were sufficient to bypass quiescence induced by ΔNp63α and other quiescence-inducing stimuli. These studies identify a novel mechanism by which ΔNp63α preserves long-term replicative capacity by promoting cellular quiescence and identify the Notch signaling pathway as a mediator of multiple quiescence-inducing stimuli, including ΔNp63α expression.

Open Access Article

Schedule-dependent synergy of histone deacetylase inhibitors with DNA damaging agents in small cell lung cancer

Victoria L. Luchenko, Crystal D. Salcido, Yongwei Zhang, Keli Agama, Edina Komlodi-Pasztor, Robert F. Murphy, Giuseppe Giaccone, Yves Pommier, Susan E. Bates and Lyuba Varticovski
Pages 3119 - 3128
http://dx.doi.org/10.4161/cc.10.18.17190
Abstract | PDF

Small cell lung cancer (SCLC) is an aggressive lung cancer subtype in need of better therapies. Histone deacetylase inhibitors (HDIs) promote increased lysine acetylation in nucleosomal histones and are thought to relax chromatin, thereby allowing increased access of transcription factors and DNA damaging agents alike to DNA. We studied whether two HDIs, belinostat and romidepsin, could be effectively combined with cisplatin or etoposide (VP-16) for SCLC cells. Analysis of cell survival and synergy was performed using CalcuSyn mathematical modeling to calculate a combination index. Immunostaining of γH2AX was performed to evaluate persistence of DNA damage following simultaneous or sequential exposure. Based on CalcuSyn modeling, HDIs synergized with DNA damaging agents only when added simultaneously. An additive-to-antagonistic effect was seen with HDI pretreatment for 24 h or with addition after cisplatin or etoposide. Furthermore, pretreatment with HDIs resulted in normalization of cell cycle and reduced PARP degradation as compared with simultaneous treatment. The increase in γH2AX phosphorylation confirmed that simultaneous but not sequential treatment enhanced double-stranded DNA breaks. These results suggest that DNA relaxation is not required for synergy of HDIs with DNA damaging agents, and that scheduling of drug administration will be critical for rational development of clinical protocols.

Open Access Article

The tumor suppressor tuberin regulates mitotic onset through the cellular localization of cyclin B1

Elizabeth Fidalgo da Silva, Shora B. Ansari, Jiamila Maimaiti, Elizabeth A. Barnes, Monica Kong-Beltran, Daniel J. Donoghue and Lisa A. Porter
Pages 3129 - 3139
http://dx.doi.org/10.4161/cc.10.18.17296
Abstract | PDF

Tuberous sclerosis is a multi-organ disorder characterized by the formation of benign tumors, called hamartomas, which affects more than 1 million people worldwide. The syndrome is initiated by a mutation in one of two tumor suppressor genes, TSC1 or TSC2, that encode for the proteins hamartin and tuberin, respectively. Herein, we demonstrate that tuberin binds and regulates the G₂/M cyclin, cyclin B1. We have determined that this binding region encompasses a mutational hotspot within tuberin that is implicated in some of the most severe cases of TS. Mimicking a mutation found in a subset of patients with tuberous sclerosis, we found a significant reduction in the binding between tuberin and cyclin B1. Functionally, our data supports that tuberin plays a role in regulating the cellular localization of cyclin B1. These results demonstrate a novel and clinically relevant mechanism, where tuberin functions in mitotic onset.

Open Access Article

Raptor, a positive regulatory subunit of mTOR complex 1, is a novel phosphoprotein of the rDNA transcription machinery in nucleoli and chromosomal nucleolus organizer regions (NORs)

Alejandro Vazquez-Martin, Sílvia Cufí, Cristina Oliveras-Ferraros and Javier A. Menendez
Pages 3140 - 3152
http://dx.doi.org/10.4161/cc.10.18.17376
Abstract | PDF

Raptor is the key scaffolding protein that recruits mTOR substrates to rapamycin-sensitive mTOR complex 1 (mTORC1), a molecular integrator of mitogenic and nutrient/energy environmental inputs into protein translation and cell growth. Although Raptor phosphorylation on various sites is pivotal in the regulation of mTORC1 activity, it remains to be elucidated whether site-specific phosphorylation differentially distributes Raptor to unique subcellular compartments. When exploring the spatiotemporal cell cycle dynamics of six different phospho (P)-Raptor isoforms (Thr⁷⁰⁶, Ser⁷²², Ser⁸⁶³, Ser⁷⁹² and Ser⁸⁷⁷), a number of remarkable events differentially defined a topological resetting of P-RaptorThr706 on interphasic and mitotic chromosomes. In interphase nuclei, P-Raptor^Thr706 co-localized with fibrillarin, a component of the nucleolar small nuclear ribonucleoprotein particle, as well as with RNA polymerase I, the enzyme that transcribes nucleolar rRNA. Upon Actinomycin D-induced nucleolar segregation and disaggregation, P-RaptorThr706 was excluded from the nucleolus to accumulate at discrete nucleoplasmic bodies. During mitosis, CDK1 inhibition-induced premature assembly of nucleoli relocated fibrillarin to the surrounding regions of chromosomal-associated P-Raptor^Thr706, suggesting that a subpopulation of mitotic P-Raptor^Thr706 remained targeted at chromosomal loops of rDNA or nuclear organizer regions (NORs). At the end of mitosis and cytokinesis, when reassembly of incipient nucleoli begins upon NORs activation of rDNA transcription, fibrillarin spatially reorganized with P-Raptor^Thr706 to give rise to daughter nucleoli. Treatment with IGF1 exclusively hyperactivated nuclear P-Raptor^Ser706 and concomitantly promoted Ser²⁴⁸¹ autophosphorylation of mTOR, which monitors mTORC1-associated catalytic activity. Nucleolar- and NOR-associated P-Raptor^Ser706 may physically link mTORC1 signaling to ever-growing nucleolus plurifunctionality including ribosome biogenesis, cell stress sensor and cell cycle/aging control.

Open Access Article

SIRT6 overexpression induces massive apoptosis in cancer cells but not in normal cells

Michael Van Meter, Zhiyong Mao, Vera Gorbunova and Andrei Seluanov
Pages 3153 - 3158
http://dx.doi.org/10.4161/cc.10.18.17435
Abstract | PDF

Emerging evidence suggests that Sirtuin 6 (SIRT6) functions as a longevity assurance gene by promoting genomic stability, regulating metabolic processes and attenuating inflammation. Here, we examine the effect of SIRT6 activation on cancer cells. We show that SIRT6 overexpression induces massive apoptosis in a variety of cancer cell lines but not in normal, non-transformed cells. This cell death requires the mono-ADP-ribosyltransferase but not the deacetylase activity of SIRT6 and is mediated by the activation of both the p53 and p73 apoptotic signaling cascades in cancer cells by SIRT6. These results suggest that SIRT6 is an attractive target for pharmacological activation in cancer treatment.

Open Access Article

Lipid droplet formation protects against gluco/lipotoxicity in Candida parapsilosis: An essential role of fatty acid desaturase Ole1

Long Nam Nguyen and Joshua D. Nosanchuk
Pages 3159 - 3167
http://dx.doi.org/10.4161/cc.10.18.16932
Abstract | PDF

Elevated levels of glucose and lipids can result in cellular dysfunction in eukaryotic cells ranging from Saccharomyces cerevisiae yeasts to human cells. Moreover, glucotoxicity and lipotoxicity can cause cell death, although the mechanism(s) for lethality is unclear. In the present study, we utilized Candida parapsilosis fatty acid desaturase (OLE1) and fatty acid synthase (FAS2) gene deletion mutants and wild-type (WT) yeast cells to unravel the relationship to glucose and lipid induced cell death in eukaryotic cells. Incubation of WT yeast cells with glucose led to the rapid accumulation of lipid droplets, whereas lipid droplet formation was severely impaired in yeast cells with deletion of OLE1 (ole1Δ/Δ) or FAS2 (fas2Δ/Δ). Interestingly, ole1Δ/Δ yeast cells died within hours in a 1% glucose medium without fatty acid supplementation, whereas the WT or fas2Δ/Δ yeast cells did not. In glucose medium, ole1Δ/Δ yeast cells accumulated saturated fatty acids, while fas2Δ/Δ did not. Addition of saturated fatty acids (e.g., palmitic acid) enhanced ole1Δ/Δ yeast cell death, whereas the addition of unsaturated fatty acids (e.g., oleic or palmitoleic acid) rescued cell death. Furthermore, palmitic acid and glucose medium induced apopotic cell death in ole1Δ/Δ yeast cells, which was dependent on mitochondrial function. Thus, our results show that glucotoxicity is directly linked to lipotoxicity, which we demonstrate is mediated by mitochondrial function.

Open Access Article

Erlotinib antagonizes constitutive activation of SRC family kinases and mTOR in acute myeloid leukemia

Simone Boehrer, Lorenzo Galluzzi, Elodie Lainey, Cyrielle Bouteloup, Maximilien Tailler, Francis Harper, Gérard Pierron, Lionel Adès, Sylvain Thépot, Marie Sébert, Claude Gardin, Stéphane de Botton, Pierre Fenaux and Guido Kroemer
Pages 3168 - 3175
http://dx.doi.org/10.4161/cc.10.18.16599
Abstract | PDF

Tyrosine kinases such as SRC family kinases (SFKs) as well as the mammalian target of rapamycin (mTOR) serine/threonine kinase are often constitutively activated in acute myeloid leukemia (AML) and hence constitute potential therapeutic targets. Here we demonstrate that the epidermal growth factor receptor (EGFR) inhibitor erlotinib, which has previously been shown to mediate antiproliferative/cytotoxic off-target effects in myelodysplastic syndrome (MDS) and AML blasts, reduces SFK overactivation. Erlotinib induced an arrest in the G₁ phase of the cell cycle that, in cells with constitutive SFK activation, could be recapitulated by chemical inhibition of SFKs with 3-(4-chlorophenyl)1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-α]pyrimidin-4-amine (PP2). Moreover, erlotinib inhibited the phosphorylation of mTOR targets like p70^SK6, stimulated the maturation of the autophagic marker LC3 and promoted the formation of autophagosomes. Notably, PP2 and the mTOR inhibitor rapamycin had a similar cell cycle-arresting activity to erlotinib, but neither of these compounds alone induced significant levels of cell death. Altogether, these results suggest that the therapeutic off-target effect of erlotinib may be linked to, yet cannot be entirely explained by, the inhibition of oncogenic signaling via SFKs and mTOR. Thus, combination therapies with erlotinib and rapamycin might be beneficial for MDS and AML patients.

Open Access Article

MDM2 promotes SUMO-2/3 modification of p53 to modulate transcriptional activity

Maren H. Stindt, Stephanie A. Carter, Arnaud M. Vigneron, Kevin M. Ryan and Karen H. Vousden
Pages 3176 - 3188
http://dx.doi.org/10.4161/cc.10.18.17436
Abstract | PDF

The tumor suppressor p53 is extensively regulated by post-translational modification, including modification by the small ubiquitin-related modifier SUMO. We show here that MDM2, previously shown to promote ubiquitin, Nedd8 and SUMO-1 modification of p53, can also enhance conjugation of endogenous SUMO-2/3 to p53. Sumoylation activity requires p53-MDM2 binding but does not depend on an intact RING finger. Both ARF and L11 can promote SUMO-2/3 conjugation of p53. However, unlike the previously described SUMO-1 conjugation of p53 by an MDM2-ARF complex, this activity does not depend on the ability of MDM2 to relocalize to the nucleolus. Interestingly, the SUMO consensus is not conserved in mouse p53, which is therefore not modified by SUMO-2/3. Finally, we show that conjugation of SUMO-2/3 to p53 correlates with a reduction of both activation and repression of a subset of p53-target genes.

Open Access Article

Characterization of novel antisense HIF-1α transcripts in human cancers

Davide Bertozzi, Raffaella Iurlaro, Olivier Sordet, Jessica Marinello, Nadia Zaffaroni and Giovanni Capranico
Pages 3189 - 3197
http://dx.doi.org/10.4161/cc.10.18.17183
Abstract | PDF

Whole transcriptome analyses have revealed new classes of long ncRNA (lncRNA), the functions of which are however largely unknown. Recently, we showed that the antitumor DNA topoisomerase I (Top1) inhibitor camptothecin (CPT) increases the cellular levels of two antisense lncRNAs at the 5' (5'aHIF-1α) and 3' (3'aHIF-1α) ends of the human HIF-1α gene. To gain insights into their functions, we have here determined structural and functional aspects of the two antisense RNAs in human cancer cell lines and kidney tumor specimen. We found that the antisense transcripts are activated in response to partially different kinds of stress, and that the 5'aHIF-1α has a 5'Cap and a poly(A+) tail, while the 3'aHIF-1α is known to lack both modifications. Cell fractionation experiments showed that 5' and 3' antisense RNAs are nuclear transcripts. Further analyses by RNA-FISH showed that the 5'aHIF-1α accumulates at the perinuclear cellular compartment and co-localizes with the nuclear pore complex Nup62 protein, suggesting a role in nuclear membrane trafficking. Finally, we provide evidence that the studied antisense lncRNAs are expressed in human kidney cancer tissues, highlighting their possible roles in cancer development. Altogether, our findings may suggest a novel function of 5'aHIF-1α in membrane transport that may regulate the cancer-relevant HIF-1α pathway.

Open Access Article

Mesenchymal stem cell-secreted soluble signaling molecules potentiate tumor growth

Wei Zhu, Ling Huang, Yahong Li, Hui Qian, Xiuhong Shan, Yongmin Yan, Fei Mao, Xiaosheng Wu and Wen-Rong Xu
Pages 3198 - 3207
http://dx.doi.org/10.4161/cc.10.18.17638
Abstract | PDF

In previous studies, we and others have shown that bone marrow mesenchymal stem cells (MSCs) are recruited to sites of growing tumors and promote tumor growth in mouse xenograft models, suggesting that interactions between MSCs and tumor cells may play an important role in this process. However, the exact mechanism remains unclear. In the present study, we investigated whether the physical presence or the continuous presence of MSCs is required for enhanced tumor growth, and we found that pretreatment of tumor cells SGC-7901 with a single dose of human MSC-conditioned medium (hMSC-CM) in vitro is sufficient to potentiate tumor growth comparable to the effect of MSC co-injection in vivo in mouse xenograft models. We further showed that significant tumor modifying activity is present in post-ultracentrifigation soluble fraction. Biochemical analysis suggests that hMSC-CM induces the expression of VEGF of tumor cells as well as the activation of RhoA-GTPase and ERK1/2. Furthermore, hMSC-CM-enhanced tumor growth is sustainable in serial transplantation, suggesting that MSC-secreted factors have profound effects on “reprogramming” of tumor growth. Our data provide new insights into the way in which MSCs modify tumor growth and offer a new and exciting opportunity to develop effective therapeutics for intercepting tumor progression.




LETTER TO THE EDITOR

Open Access Article

Drug-induced inhibition of tubulin polymerization induces mitochondrion-mediated apoptosis in yeast

Vanessa Palermo, Luisa Pieri, Romano Silvestri, Giuseppe La Regina, Claudio Falcone and Cristina Mazzoni
Pages 3208 - 3209
http://dx.doi.org/10.4161/cc.10.18.16514
PDF