Table of Contents

Volume 11, Issue 18

  September 15, 2012

  Pages 3339 - 3518

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 Issue Catalogue (MARC XML)

EDITORIALS: CELL CYCLE FEATURES

Open Access Article

A novel G₁ checkpoint mediated by the p57 CDK inhibitor and p38 SAPK promotes cell survival upon stress

Manel Joaquin, Albert Gubern and Francesc Posas
Pages 3339 - 3340
http://dx.doi.org/10.4161/cc.21840
Abstract | Full Text | PDF

Comment on: Joaquin M, et al. EMBO J 2012; 31:2952-64.

Open Access Article

The oncogenic transcription factor FOXM1 and anticancer therapy

Andrei L. Gartel
Pages 3341 - 3342
http://dx.doi.org/10.4161/cc.21841
Abstract | Full Text | PDF

Comment on: Halasi M,et al. PLoS One 2012; 7:e31761.

Open Access Article

A general requirement for FcγRIIB co-engagement of agonistic anti-TNFR antibodies

Fubin Li and Jeffrey V. Ravetch
Pages 3343 - 3344
http://dx.doi.org/10.4161/cc.21842
Abstract | Full Text | PDF

Comment on: Li F, et al. Proc Natl Acad Sci USA 2012; 109:10966-71.

Open Access Article

How a mismatch repair enzyme balances the needs for efficient lesion processing and minimal action on undamaged DNA

Alexander C. Drohat, Edwin Pozharski and Atanu Maiti
Pages 3345 - 3346
http://dx.doi.org/10.4161/cc.21843
Abstract | Full Text | PDF

Comment on: Maiti A, et al. Proc Natl Acad Sci USA 2012; 109:8091-6.

Open Access Article

How not to get cross(ed): A novel role for FANCM orthologs in meiotic recombination

Alexander Lorenz and Matthew C. Whitby
Pages 3347 - 3348
http://dx.doi.org/10.4161/cc.21844
Abstract | Full Text | PDF

Comment on: Lorenz A, et al. Science 2012; 336:1585-8.

Open Access Article

TLS/FUS: A protein in cancer and ALS

Adelene Y. Tan and James L. Manley
Pages 3349 - 3350
http://dx.doi.org/10.4161/cc.21875
Abstract | Full Text | PDF

Comment on: Tan AY, et al. Proc Natl Acad Sci USA 2012; 109:6030-5.

Open Access Article

Combination of isoform-selective histone/protein deacetylase inhibitors improves Foxp3+ T-regulatory cell function

Ulf H. Beier, Liqing Wang and Wayne W. Hancock
Pages 3351 - 3352
http://dx.doi.org/10.4161/cc.21876
Abstract | Full Text | PDF

Comment on: Beier UH, et al. Sci Signal 2012; 5:ra45.




CELL CYCLE NEWS & VIEWS

Open Access Article

The fox and the fat: An unexpected new treatment for brain tumors

Edward M. Johnson
Page 3353
http://dx.doi.org/10.4161/cc.21848
Abstract | Full Text | PDF

Comment on: Wilk A, et al. Cell Cycle 2012; 11:2660-71.

Open Access Article

Directing p53 to induce autophagy

Lindsey D. Mayo
Page 3354
http://dx.doi.org/10.4161/cc.21849
Abstract | Full Text | PDF

Comment on: Naidu SR, et al. Cell Cycle 2012; 11:2717-28.

Open Access Article

Doubling the deck: Tetraploidy induces chromosome shuffling and cancer

Joshua M. Nicholson and Daniela Cimini
Page 3355
http://dx.doi.org/10.4161/cc.21850
Abstract | Full Text | PDF

Comment on: Lv L, et al. Cell Cycle 2012; 11:2864-75.

Open Access Article

Switch of FANCL, a key FA-BRCA component, between tumor suppressor and promoter by alternative splicing

Chengfu Yuan, Ningzhi Xu and Joshua Liao
Page 3356
http://dx.doi.org/10.4161/cc.21852
Abstract | Full Text | PDF

Comment on: Panneerselvam J, et al. Cell Cycle 2012; 11:2947-55.

Open Access Article

New evidence that SAC can tolerate misaligned chromosomes in mouse oocytes

Silvia Polakova, Miroslava Pozgajova and Juraj Gregan
Page 3357
http://dx.doi.org/10.4161/cc.21851
Abstract | Full Text | PDF

Comment on: Sebestova J, et al. Cell Cycle 2012; 11:3011-8.




EXTRA VIEWS

The BTB-ZF transcription factors

Owen M. Siggs and Bruce Beutler
Pages 3358 - 3369
http://dx.doi.org/10.4161/cc.21277
Abstract | Full Text | PDF

The BTB-ZF (broad-complex, tramtrack and bric-à-brac - zinc finger) proteins are encoded by at least 49 genes in mouse and man and commonly serve as sequence-specific silencers of gene expression. This review will focus on the known physiological functions of mammalian BTB-ZF proteins, which include essential roles in the development of the immune system. We discuss their function in terminally differentiated lymphocytes and the progenitors that give rise to them, their action in hematopoietic malignancy and roles beyond the immune system.

Combination treatment with bortezomib and thiostrepton is effective against tumor formation in mouse models of DEN/PB-induced liver carcinogenesis

Ming Wang, Marianna Halasi, Kasim Kabirov, Aryamitra Banerjee, Jennifer Landolfi, Alexander V. Lyubimov and Andrei L. Gartel
Pages 3370 - 3372
http://dx.doi.org/10.4161/cc.21290
Abstract | Full Text | PDF

Nanoparticle-encapsulated thiazole antibiotic, thiostrepton, has been shown to be an effective agent for inhibiting tumor growth in solid tumor models through the inhibition of proteasomal activity by the induction of apoptosis in cancer cells. Here, we show the efficacy of thiostrepton-micelles in inhibiting tumor growth in a DEN/PB-induced liver cancer model. We also demonstrate an enhanced anticancer effect of the combination treatment of thiostrepton with bortezomib, another proteasome inhibitor in this liver cancer model.

Open Access Article

Convergent signaling in the regulation of connective tissue growth factor in malignant mesothelioma: TGFβ signaling and defects in the Hippo signaling cascade

Makiko Fujii, Hayao Nakanishi, Takeshi Toyoda, Ichidai Tanaka, Yutaka Kondo, Hirotaka Osada and Yoshitaka Sekido
Pages 3373 - 3379
http://dx.doi.org/10.4161/cc.21397
Abstract | Full Text | PDF

Malignant mesothelioma (MM) is a neoplasm that arises from serosal surfaces of the pleural, peritoneal and pericardial cavities with worldwide incidence, much of which is caused by asbestos exposure. Patients suffer from pain and dyspnea due to direct invasion of the chest wall, lungs and vertebral or intercostal nerves by masses of thick fibrotic tumors. Although there has been recent progress in the clinical treatment, current therapeutic approaches do not provide satisfactory results. Therefore, development of a molecularly targeted therapy for MM is urgently required. Our recent studies suggest that normal mesothelial and MM cell growth is promoted by TGFβ, and that TGFβ signaling together with intrinsic disturbances in neurofibromatosis type 2 (NF2) and Hippo signaling cascades in MM cells converges upon further expression of connective tissue growth factor (CTGF). The formation of a YAP-TEAD4–Smad3-p300 complex on the specific CTGF promoter site with an adjacent TEAD and Smad binding motif is a critical and synergistic event caused by the dysregulation of these two distinct cascades. Furthermore, we demonstrated the functional importance of CTGF through the mouse studies and human histological analyses, which may elucidate the clinical features of MM with severe fibrosis in the thoracic cavity.

Oncogenic transcription factors as master regulators of chromatin topology: A new role for ERG in prostate cancer

Olivier Elemento, Mark A. Rubin and David S. Rickman
Pages 3380 - 3383
http://dx.doi.org/10.4161/cc.21401
Abstract | Full Text | PDF

The three-dimensional (3D) conformation of the genome is known to be structured and to affect gene transcription, but how chromatin conformation changes in diseases such as cancer is poorly understood. Similarly, oncogenic transcription factors bind to thousands of sites in the genome without a clear transcriptional role on nearby genes. Could these factors play a non-transcriptional role in promoting tumor progression by restructuring the shape of the genome? To address this question, we recently performed unbiased high-resolution mapping of intra- and inter-chromosome interactions upon overexpression of ERG, an oncogenic transcription factor frequently overexpressed in prostate cancer as a result of a gene fusion. By integrating data from genome-wide chromosome conformation capture (Hi-C), ERG binding and gene expression, we have demonstrated that oncogenic transcription factor overexpression is associated with global, reproducible and functionally coherent changes in chromatin organization. Perhaps more importantly, we have identified novel genomic alterations associated with ERG overexpression. These results suggest a yet unappreciated role for transcription factors in promoting genomic alterations through their effect on chromatin architecture.

TOR under stress: Targeting TORC1 by Rho1 GTPase

Yan Gonghong, Yumei Lai and Yu Jiang
Pages 3384 - 3388
http://dx.doi.org/10.4161/cc.21461
Abstract | Full Text | PDF

In the yeast Saccharomyces cerevisiae, small GTPase Rho1 controls polarized actin distribution and cell wall expansion in response to many different environmental and intracellular stimuli. Its activity is essential for cell survival and adaptation under various stress conditions. A recent study identified the TOR complex 1 (TORC1), a central regulator in cell growth and metabolism, as a direct target of the small GTPase. This novel crosstalk extends the signaling network of Rho1 into many TORC1-dependent processes and sheds light on how yeast cells coordinate polarized spatial expansion with mass increase.




PERSPECTIVE

Open Access Article

Emerging role of DYRK family protein kinases as regulators of protein stability in cell cycle control

Walter Becker
Pages 3389 - 3394
http://dx.doi.org/10.4161/cc.21404
Abstract | Full Text | PDF

Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) constitute an evolutionarily conserved family of protein kinases with key roles in the control of cell proliferation and differentiation. Members of the DYRK family phosphorylate many substrates, including critical regulators of the cell cycle. A recent report revealed that human DYRK2 acts as a negative regulator of G₁/S transition by phosphorylating c-Jun and c-Myc, thereby inducing ubiquitination-mediated degradation. Other DYRKs also function as cell cycle regulators by modulating the turnover of their target proteins. DYRK1B can induce reversible cell arrest in a quiescent G₀ state by targeting cyclin D1 for proteasomal degradation and stabilizing p27^Kip1. The DYRK2 ortholog of C. elegans, MBK-2, triggers the proteasomal destruction of oocyte proteins after meiosis to allow the mitotic divisions in embryo development. This review summarizes the accumulating results that provide evidence for a general role of DYRKs in the regulation of protein stability.




REPORTS

Spartan/C1orf124 is important to prevent UV-induced mutagenesis

Yuka Machida, Myoung Shin Kim and Yuichi J. Machida
Pages 3395 - 3402
http://dx.doi.org/10.4161/cc.21694
Abstract | Full Text | PDF

Uninterrupted replication across damaged DNA is critical to prevent replication fork collapse and resulting double-strand DNA breaks. Rad18-mediated PCNA ubiquitination is a crucial event that triggers a number of downstream pathways important for lesion bypass. Here, we report characterization of Spartan, an evolutionarily conserved protein containing a PCNA-interacting peptide motif, called a PIP box, and a UBZ4 ubiquitin-binding domain. Spartan is a nuclear protein and forms DNA damage-induced foci that colocalize with markers for stalled DNA replication. Focus formation of Spartan requires its PIP-box and the UBZ4 domain and is dependent on Rad18 and the PCNA ubiquitination site, indicating that Spartan is recruited to ubiquitinated PCNA. Spartan depletion results in increased mutagenesis during replication of UV-damaged DNA. Taken together, our data suggest that Spartan is recruited to sites of stalled replication via ubiquitinated PCNA and plays an important role to prevent mutations associated with replication of damaged DNA.

Featured Article - FREE

Metabolic remodeling of the tumor microenvironment: Migration stimulating factor (MSF) reprograms myofibroblasts toward lactate production, fueling anabolic tumor growth

Valentina Carito, Gloria Bonuccelli, Ubaldo E. Martinez-Outschoorn, Diana Whitaker-Menezes, Maria Cristina Caroleo, Erika Cione, Anthony Howell, Richard G. Pestell, Michael P. Lisanti and Federica Sotgia
Pages 3403 - 3414
http://dx.doi.org/10.4161/cc.21701
Abstract | Full Text | PDF

Migration stimulating factor (MSF) is a genetically truncated N-terminal isoform of fibronectin that is highly expressed during mammalian development in fetal fibroblasts, and during tumor formation in human cancer-associated myofibroblasts. However, its potential functional role in regulating tumor metabolism remains unexplored. Here, we generated an immortalized fibroblast cell line that recombinantly overexpresses MSF and studied their properties relative to vector-alone control fibroblasts. Our results indicate that overexpression of MSF is sufficient to confer myofibroblastic differentiation, likely via increased TGF-b signaling. In addition, MSF activates the inflammation-associated transcription factor NFκB, resulting in the onset of autophagy/mitophagy, thereby driving glycolytic metabolism (L-lactate production) in the tumor microenvironment. Consistent with the idea that glycolytic fibroblasts fuel tumor growth (via L-lactate, a high-energy mitochondrial fuel), MSF fibroblasts significantly increased tumor growth, by up to 4-fold. Mechanistic dissection of the MSF signaling pathway indicated that Cdc42 lies downstream of MSF and fibroblast activation. In accordance with this notion, Cdc42 overexpression in immortalized fibroblasts was sufficient to drive myofibroblast differentiation, to provoke a shift towards glycolytic metabolism and to promote tumor growth by up to 2-fold. In conclusion, the MSF/Cdc42/NFκB signaling cascade may be a critical druggable target in preventing “Warburg-like” cancer metabolism in tumor-associated fibroblasts. Thus, MSF functions in the metabolic remodeling of the tumor microenvironment by metabolically reprogramming cancer-associated fibroblasts toward glycolytic metabolism.

Androgen receptor serine 81 mediates Pin1 interaction and activity

Raffaele La Montagna, Isabella Caligiuri, Pasquale Maranta, Chiara Lucchetti, Luca Esposito, Marco G. Paggi, Giuseppe Toffoli, Flavio Rizzolio and Antonio Giordano
Pages 3415 - 3420
http://dx.doi.org/10.4161/cc.21730
Abstract | Full Text | PDF

Hormone-dependent tumors are characterized by deregulated activity of specific steroid receptors, allowing aberrant expression of many genes involved in cancer initiation, progression and metastasis. In prostate cancer, the androgen receptor (AR) protein has pivotal functions, and over the years it has been the target of different drugs. AR is a nuclear receptor whose activity is regulated by a phosphorylation mechanism controlled by hormone and growth factors. Following phosphorylation, AR interacts with many cofactors that closely control its function. Among such cofactors, Pin1 is a peptidyl-prolyl isomerase that is involved in the control of protein phosphorylation and has a prognostic value in prostate cancer. In the present study, we demonstrate that ARSer81 is involved in the interaction with Pin1, and that this interaction is important for the transcriptional activity of AR. Since Pin1 expression positively correlates with tumor grade, our results suggest that Pin1 can participate in this process by modulating AR function.

The Mck1 GSK-3 kinase inhibits the activity of Clb2-Cdk1 post-nuclear division

Jennifer McQueen, Dewald van Dyk, Barry Young, Chris Loewen and Vivien Measday
Pages 3421 - 3432
http://dx.doi.org/10.4161/cc.21731
Abstract | Full Text | PDF

The glycogen synthase kinase-3 homolog, Mck1, has been implicated in many cellular functions, from sporulation to calcium stress response in budding yeast. Here, we report a novel function for Mck1 in the inhibition of Clb2-Cdk1 activity post nuclear division. Clb2-Cdk1, the major mitotic cyclin-Cdk complex in yeast, accumulates before anaphase and must be inhibited in telophase for cells to exit mitosis and enter into the next cell cycle. We show that the mck1Δ mutant is highly sensitive to increased Clb2-Cdk1 activity caused either by overexpression of Clb2 or the Cdk1-activating phosphatase Mih1. Deletion of the Cdk1 inhibitory kinase, SWE1, in combination with a mck1Δ mutant results in a synthetic growth defect, suggesting that Mck1 and Swe1 function in parallel pathways to inhibit Clb2-Cdk1. We find that mck1Δ strains have a delay in mitotic exit as well as elevated levels of Clb2-Cdk1 activity post-nuclear division. Using a co-immunoprecipitation assay, we identify a physical interaction between Mck1 and both Clb2 and Mih1. Finally, we demonstrate that phosphorylation of purified Clb2 by Cdk1 is inhibited by catalytically active Mck1 but not catalytically inactive Mck1 in vitro. We propose that Mck1 inhibits the activity of Clb2-Cdk1 via interaction with Clb2. The mammalian glycogen synthase kinase-3 homolog has been implicated in cyclin inhibition, suggesting a conserved cell cycle function for both yeast and mammalian glycogen synthase kinases.

p53 negatively regulates Aurora A via both transcriptional and posttranslational regulation

Chun-Chi Wu, Tsung-Ying Yang, Chang-Tze Ricky Yu, Liem Phan, Cristina Ivan, Anil K. Sood, Shih-Lan Hsu and Mong-Hong Lee
Pages 3433 - 3442
http://dx.doi.org/10.4161/cc.21732
Abstract | Full Text | PDF

p53 plays an important role in mitotic checkpoint, but what its role is remains enigmatic. Aurora A is a Ser/Thr kinase involved in correcting progression of mitosis. Here, we show that p53 is a negative regulator for Aurora A. We found that p53 deficiency leads to Aurora A elevation. Ectopic expression of p53 or DNA damage-induced expression of p53 can suppress the expression of Aurora A. Mechanistic studies show that p53 is a negative regulator for Aurora A expression through both transcriptional and posttranslational regulation. p53 knockdown in cancer cells reduces the level of p21, which, in turn, increases the activity of CDK2 followed by induction of Rb1 hyperphosphorylation and its dissociation with transcriptional factor E2F3. E2F3 can bind to Aurora A gene promoter, potentiating Aurora A gene expression and p53 deficiency, enhancing the binding of E2F3 on Aurora A promoter. Also, p53 deficiency leads to decelerating Aurora A’s turnover rate, due to the fact that p53 deficiency causes the downregulation of Fbw7α, a component of E3 ligase of Aurora A. Consistently, p53 knockdown-mediated Aurora A elevation is mitigated when Fbw7α is ectopically expressed. Thus, p53-mediated Aurora A degradation requires Fbw7α expression. Significantly, inverse correlation between p53 and Aurora A elevation is translated into the deregulation of centrosome amplification. p53 knockdown leads to high percentages of cells with abnormal amplification of centrosome. These data suggest that p53 is an important negative regulator of Aurora A, and that loss of p53 in many types of cancer could lead to abnormal elevation of Aurora A and dysregulated mitosis, which provides a growth advantage for cancer cells.

Lithocholic acid extends longevity of chronologically aging yeast only if added at certain critical periods of their lifespan

Michelle T. Burstein, Pavlo Kyryakov, Adam Beach, Vincent R. Richard, Olivia Koupaki, Alejandra Gomez-Perez, Anna Leonov, Sean Levy, Forough Noohi and Vladimir I. Titorenko
Pages 3443 - 3462
http://dx.doi.org/10.4161/cc.21754
Abstract | Full Text | PDF

Our studies revealed that LCA (lithocholic bile acid) extends yeast chronological lifespan if added to growth medium at the time of cell inoculation. We also demonstrated that longevity in chronologically aging yeast is programmed by the level of metabolic capacity and organelle organization that they developed before entering a quiescent state and, thus, that chronological aging in yeast is likely to be the final step of a developmental program progressing through at least one checkpoint prior to entry into quiescence. Here, we investigate how LCA influences longevity and several longevity-defining cellular processes in chronologically aging yeast if added to growth medium at different periods of the lifespan. We found that LCA can extend longevity of yeast under CR (caloric restriction) conditions only if added at either of two lifespan periods. One of them includes logarithmic and diauxic growth phases, whereas the other period exists in early stationary phase. Our findings suggest a mechanism linking the ability of LCA to increase the lifespan of CR yeast only if added at either of the two periods to its differential effects on various longevity-defining processes. In this mechanism, LCA controls these processes at three checkpoints that exist in logarithmic/diauxic, post-diauxic and early stationary phases. We therefore hypothesize that a biomolecular longevity network progresses through a series of checkpoints, at each of which (1) genetic, dietary and pharmacological anti-aging interventions modulate a distinct set of longevity-defining processes comprising the network; and (2) checkpoint-specific master regulators monitor and govern the functional states of these processes.

4E-BP1 participates in maintaining spindle integrity and genomic stability via interacting with PLK1

Zeng-Fu Shang, Lan Yu, Bing Li, Wen-Zhi Tu, Yu Wang, Xiao-Dan Liu, Hua Guan, Bo Huang, Wei-Qing Rang and Ping-Kun Zhou
Pages 3463 - 3471
http://dx.doi.org/10.4161/cc.21770
Abstract | Full Text | PDF

The essential function of eIF4E-binding protein 1 (4E-BP1) in translation initiation has been well established; however, the role of 4E-BP1 in normal cell cycle progression is coming to attention. Here, we revealed the role of 4E-BP1 on mitotic regulation and chromosomal DNA dynamics during mitosis. First, we have observed the co-localization of the phosphorylated 4E-BP1 at T37/46 with Polo-like kinase 1 (PLK1) at the centrosomes during. Depression of 4E-BP1 by small interfering RNA in HepG2 or HeLa cells resulted in an increased outcome of polyploidy and aberrant mitosis, including chromosomal DNA misaligned and multi-polar spindles or multiple centrosomes. We observed that 4E-BP1 interacted with PLK1 directly in vitro and in vivo in mitotic cells, and the C-terminal aa 77–118 of 4E-BP1 mediates its interaction with PLK1. PLK1 can phosphorylate 4E-BP1 in vitro. Furthermore, the depletion of 4E-BP1 sensitized HepG2 and HeLa cells to the microtubule disruption agent paclitaxel. These results demonstrate that 4E-BP1, beyond its role in translation regulation, can function as a regulator of mitosis via interacting with PLK1, and possibly plays a role in genomic stability maintaining.

Featured Article - FREE

Independent transcriptional reprogramming and apoptosis induction by cisplatin

Lorenzo Galluzzi, Ilio Vitale, Laura Senovilla, Tobias Eisenberg, Didac Carmona-Gutiérrez, Erika Vacchelli, Thomas Robert, Hugues Ripoche, Nora Jägemann, Caroline Paccard, Nicolas Servant, Philippe Hupé, Vladimir Lazar, Philippe Dessen, Emmanuel Barillot, Hans Zischka, Frank Madeo and Guido Kroemer
Pages 3472 - 3480
http://dx.doi.org/10.4161/cc.21789
Abstract | Full Text | PDF

Neither the molecular mechanisms whereby cancer cells intrinsically are or become resistant to the DNA-damaging agent cisplatin nor the signaling pathways that account for cisplatin cytotoxicity have thus far been characterized in detail. In an attempt to gain further insights into the molecular cascades elicited by cisplatin (leading to resistance or underpinning its antineoplastic properties), we comparatively investigated the ability of cisplatin, C2-ceramide and cadmium dichloride, alone or in the presence of an array of mitochondrion-protective agents, to trigger the permeabilization of purified mitochondria. In addition, we compared the transcriptional response triggered by cisplatin, C2-ceramide and cadmium dichloride in non-small cell lung carcinoma A549 cells. Finally, we assessed the capacity of cisplatin, C2-ceramide and cadmium dichloride to reduce the clonogenic potential of a battery of yeast strains lacking proteins involved in the regulation of cell death, DNA damage signaling and stress management. This multipronged experimental approach revealed that cisplatin elicits signaling pathways that are for the most part “private,” i.e., that manifest limited overlap with the molecular cascades ignited by other inducers of mitochondrial apoptosis, and triggers apoptosis mainly in a transcription-independent fashion. Indeed, bona fide cisplatin-response modifiers that we have recently identified by a functional genome-wide siRNA screen are either not transcriptionally regulated during cisplatin-induced cell death or their transcriptional modulation reflects the activation of an adaptive response promoting cisplatin resistance

Effect of circadian clock mutations on DNA damage response in mammalian cells

Shobhan Gaddameedhi, Joyce T. Reardon, Rui Ye, Nuri Ozturk and Aziz Sancar
Pages 3481 - 3491
http://dx.doi.org/10.4161/cc.21771
Abstract | Full Text | PDF

The circadian clock is a global regulatory mechanism that confers daily rhythmicity on many biochemical and physiological functions, including DNA excision repair in mammalian organisms. Here, we investigated the effect of the circadian clock on the major DNA damage response pathways by using mouse cell lines mutated in genes encoding proteins in the positive (Bmal1, CLOCK) or negative (Cry 1/2, Per 1/2) arms of the transcription-translation feedback loop that generates the circadian clock. We find that cells mutated in these genes are indistinguishable from wild-type in their response to UV, ionizing radiation and mitomycin C. We conclude that either the majority of DNA damage response reactions are not controlled by the circadian clock or that, even if such a control exists at the organism level, it is supplanted by homeostatic control mechanisms at the cellular level in tissue culture. We suggest that caution must be exercised in extrapolating from experiments in tissue culture to whole animals with respect to the effect of the circadian clock on cellular response to DNA damaging agents.

Overexpression of EVI1 interferes with cytokinesis and leads to accumulation of cells with supernumerary centrosomes in G_0/1 phase

Kadin Karakaya, Friederike Herbst, Claudia Ball, Hanno Glimm, Alwin Krämer and Harald Löffler
Pages 3492 - 3503
http://dx.doi.org/10.4161/cc.21801
Abstract | Full Text | PDF

Ectopic viral integration site 1 (EVI1), a transcription factor frequently overexpressed in myeloid neoplasias, has been implicated in the generation of malignancy-associated centrosomal aberrations and chromosomal instability. Here, we sought to investigate the underlying cause of centrosome amplification in EVI1-overexpressing cells. We found that overexpression of EVI1-HA in U2OS cells induced supernumerary centrosomes, which were consistently associated with enlarged nuclei or binuclear cells. Live cell imaging experiments identified cytokinesis failure as the underlying cause of this phenotype. In accordance with previous reports, EVI1 overexpression induced a partial cell cycle arrest in G_0/1 phase, accompanied by elevated cyclin D1 and p21 levels, reduced Cdk2 activity and activation of the p53 pathway. Supernumerary centrosomes predominantly occurred in resting cells, as identified by low levels of the proliferation marker K_i-67, leading to the conclusion that they result from tetraploidization after cytokinesis failure and are confined to G_0/1-arrested tetraploid cells. Depletion of p53 using siRNA revealed that further polyploidization of these cells was inhibited by the p53-dependent tetraploidy checkpoint.

Impaired adult myeloid progenitor CMP and GMP cell function in conditional c-myb-knockout mice

Yen K. Lieu and E. Premkumar Reddy
Pages 3504 - 3512
http://dx.doi.org/10.4161/cc.21802
Abstract | Full Text | PDF

The differentiation of myeloid progenitors to mature, terminally differentiated cells is a highly regulated process. Here, we showed that conditional disruption of the c-myb proto-oncogene in adult mice resulted in dramatic reductions in CMP, GMP and MEP myeloid progenitors, leading to a reduction of neutrophils, basophils, monocytes and platelets in peripheral blood. In addition, c-myb plays a critical role at multiple stages of myeloid development, from multipotent CMP and bipotent GMP to unipotent CFU-G and CFU-M progenitor cells. c-myb controls the differentiation of these cells and is required for the proper commitment, maturation and normal differentiation of CMPs and GMPs. Specifically, c-myb regulates the precise commitment to the megakaryocytic and granulo-monocytic pathways and governs the granulocytic-monocytic lineage choice. c-myb is also required for the commitment along the granulocytic pathway for early myeloid progenitor cells and for the maturation of committed precursor cells along this pathway. On the other hand, disruption of the c-myb gene favors the commitment to the monocytic lineage, although monocytic development was abnormal with cells appearing more mature with atypical CD41 surface markers. These results demonstrate that c-myb plays a pivotal role in the regulation of multiple stages in adult myelogenesis.

Multipotent nestin-expressing stem cells capable of forming neurons are located in the upper, middle and lower part of the vibrissa hair follicle

Yasuyuki Amoh, Sumiyuki Mii, Ryoichi Aki, Yuko Hamada, Katsumasa Kawahara, Robert M. Hoffman and Kensei Katsuoka
Pages 3513 - 3517
http://dx.doi.org/10.4161/cc.21803
Abstract | Full Text | PDF

We have previously demonstrated that the neural stem-cell marker nestin is expressed in hair follicle stem cells. Nestin-expressing cells were initially identified in the hair follicle bulge area (BA) using a transgenic mouse model in which the nestin promoter drives the green fluorescent protein (ND-GFP). The hair-follicle ND-GFP-expressing cells are keratin 15-negative and CD34-positive and could differentiate to neurons, glia, keratinocytes, smooth muscle cells and melanocytes in vitro. Subsequently, we showed that the nestin-expressing stem cells could affect nerve and spinal cord regeneration after injection in mouse models. In the present study, we separated the mouse vibrissa hair follicle into three parts (upper, middle and lower). Each part of the follicle was cultured separately in DMEM-F12 containing B-27 and 1% methylcellulose supplemented with basic FGF. After 2 mo, the nestin-expressing cells from each of the separated parts of the hair follicle proliferated and formed spheres. Upon transfer of the spheres to RPMI 1640 medium containing 10% FBS, the nestin-expressing cells in the spheres differentiated to neurons, as well as glia, keratinocytes, smooth muscle cells and melanocytes. The differentiated cells were produced by spheres which formed from nestin-expressing cells from all segments of the hair follicle. However, the differentiation potential is greatest in the upper part of the follicle. This result is consistent with trafficking of nestin-expressing cells throughout the hair follicle from the bulge area to the dermal papilla that we previously observed. The nestin-expressing cells from the upper part of the follicle produced spheres in very large amounts, which in turn differentiated to neurons and other cell types. The results of the present study demonstrate that multipotent, nestin-expressing stem cells are present throughout the hair follicle and that the upper part of the follicle can produce the stem cells in large amounts that could be used for nerve and spinal cord repair.




ERRATUM

Open Access Article

Erratum to Issaenko OA, et al. Cell Cycle Volume 11, Issue 9; pp. 1804-17

Olga A. Issaenko and Alexander Yu Amerik
Page 3518
http://dx.doi.org/10.4161/cc.22096
Full Text | PDF