Table of Contents

Volume 10, Issue 7

  April 1, 2011

  Pages 1015 - 1167

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 Issue Catalogue (MARC XML)

EDITORIALS: CELL CYCLE FEATURES

Open Access Article

mTOR upregulation of glycolytic enzymes promotes tumor development

Xiaojun Zha, Qian Sun and Hongbing Zhang
Pages 1015 - 1016
http://dx.doi.org/10.4161/cc.10.7.15063
Abstract | PDF

Comment on: Zha X, et al. Cancer Res 2011; 71:13-8.

Open Access Article

AMP kinase signals the insulin-like growth factor system whether adequate nutrient is present to support an anabolic response

David R. Clemmons
Pages 1017 - 1018
http://dx.doi.org/10.4161/cc.10.7.15088
PDF

Open Access Article

PDK1-driven Myc signaling regulates cellular response to mTOR inhibitors

Jing Tan and Qiang Yu
Pages 1019 - 1020
http://dx.doi.org/10.4161/cc.10.7.15163
Abstract | PDF

Comment on: Tan J, et al. Cancer Cell 2010; 18:459-71

Open Access Article

Transcription of intergenic DNA deposits nucleosomes on promoter to silence gene expression

Justin A. Pruneski and Joseph A. Martens
Pages 1021 - 1022
http://dx.doi.org/10.4161/cc.10.7.15167
Abstract | PDF

Comment on: Hainer SJ, et al. Genes Dev. 2011; 25:29-40

Open Access Article

PARP-3, a DNA-dependent PARP with emerging roles in double-strand break repair and mitotic progression

Christian Boehler and Françoise Dantzer
Pages 1023 - 1024
http://dx.doi.org/10.4161/cc.10.7.15169
Abstract | PDF

Comment on: Boehler C, et al. Proc Natl Acad Sci USA 2011; 108:2783-8.




CELL CYCLE NEWS & VIEWS

Open Access Article

Partners apart: Smc6-independent DNA binding activity of Smc5 on single-strand DNA

Julien Vignard, Cyril Charbonnel and Jean-Yves Masson
Pages 1025 - 1030
http://dx.doi.org/10.4161/cc.10.7.15212
Abstract | PDF

Comment on: Roy MA, et al. Cell Cycle 2011; 10:690-700.

Open Access Article

The Mip-ing link: Mip1 links Mps1 to the actin cytoskeleton

Harold A. Fisk

http://dx.doi.org/10.4161/cc.10.7.15189
Abstract | PDF

Comment on: Mattison CP, et al. Cell Cycle 2011; 10:783-93.


Open Access Article

Polo-like kinase 1 inhibitors SBE13 and BI 2536 induce different responses in primary cells

Frank Eckerdt

http://dx.doi.org/10.4161/cc.10.7.15213
Abstract | PDF

Comment on: Keppner S, et al. Cell Cycle 2011; 10:708-720.

Open Access Article

Spc25: How the kinetochore protein plays during oocyte meiosis

Bo Xiong

http://dx.doi.org/10.4161/cc.10.7.15158
Abstract | PDF

Comment on: Sun SC, et al. Cell Cycle 2010; 9:4552-9.

Open Access Article

Should I stall or should I cycle? An inhibitor for Polo-like Kinase 1 with distinct roles in primary cells

Guido Posern

http://dx.doi.org/10.4161/cc.10.7.15214
Abstract | PDF

Comment on: Keppner S, et al. Cell Cycle 2011; 10:708-20.




EXTRA VIEWS

Open Access Article

Hes1 expression and CYLD repression are essential events downstream of Notch1 in T-cell leukemia

Teresa D’Altri, Jessica Gonzalez, Iannis Aifantis, Lluis Espinosa and Anna Bigas
Pages 1031 - 1036
http://dx.doi.org/10.4161/cc.10.7.15067
Abstract | PDF

Notch activation is a current event in T Acute Lymphoblastic Leukemia (T-ALL) but the downstream elements that are able to support Notch-dependent leukemias are not well characterized. We have recently shown that the Notch-Hes1-CYLD-NFkB axis is crucial in the maintenance of T-ALL, but detailed evaluation of the contribution of each one of these elements is still missing. Here we use a Notch1-induced leukemia in vivo model to study the effect of silencing the Notch-target gene, Hes1, or over-expressing the Hes1-target, CYLD. We here show that both strategies completely abolish the ability of constitutive active Notch1 to generate T-ALL.

Open Access Article

Epigenetic maintenance of telomere identity in Drosophila: Buckle up for the sperm ride

Raphaëlle Dubruille and Benjamin Loppin
Pages 1037 - 1042
http://dx.doi.org/10.4161/cc.10.7.15071
Abstract | PDF

A critical function of telomeres is to prevent the ligation of chromosome ends by DNA repair enzymes. In most eukaryotes, telomeric DNA consists in large arrays of G-rich tandem repeats that are recognized by DNA binding capping proteins. Drosophila telomeres are unusual as they lack short tandem repeats. However, Drosophila capping proteins can bind chromosome extremities in a DNA sequence-independent manner. This epigenetic protection of fly telomeres has been essentially studied in somatic cells where capping proteins such as HOAP or HP1 are essential in preventing chromosome end-to-end fusions. HipHop and K81 are two recently identified paralogous capping proteins with complementary expression patterns. While HipHop is involved in telomere capping in somatic cells, K81 has specialized in the protection of telomeres in post-meiotic male germ cells. Remarkably, K81 is required for the stabilization of HOAP and HP1 at telomeres during the massive paternal chromatin remodeling that occurs during spermiogenesis and at fertilization. We thus propose that the maintenance of capping proteins at Drosophila sperm telomeres is crucial for the transmission of telomere identity to the diploid zygote.



Open Access Article

Deoxyhypusine synthase haploinsufficiency attenuates acute cytokine signaling

Andrew T. Templin, Bernhard Maier, Yurika Nishiki, Sarah A. Tersey and Raghavendra G. Mirmira
Pages 1043 - 1049
http://dx.doi.org/10.4161/cc.10.7.15206
Abstract | PDF

Deoxyhypusine synthase (DHS) catalyzes the post-translational formation of the amino acid hypusine. Hypusine is unique to the eukaryotic translational initiation factor 5A (eIF5A), and is required for its functions in mRNA shuttling, translational elongation, and stress granule formation. In recent studies, we showed that DHS promotes cytokine and ER stress signaling in the islet β cell and thereby contributes to its dysfunction in the setting of diabetes mellitus. Here, we review the evidence supporting a role for DHS (and hypusinated eIF5A) in cellular stress responses, and provide new data on the phenotype of DHS knockout mice. We show that homozygous knockout mice are embryonic lethal, but heterozygous knockout mice appear normal with no evidence of growth or metabolic deficiencies. Mouse embryonic fibroblasts from heterozygous knockout mice attenuate acute cytokine signaling, as evidenced by reduced production of inducible nitric oxide synthase, but show no statistically significant defects in proliferation or cell cycle progression. Our data are discussed with respect to the utility of sub-maximal inhibition of DHS in the setting of inflammatory states, such as diabetes mellitus.

Open Access Article

The physiology and pathophysiology of rapamycin resistance: Implications for cancer

Philip A. Gruppuso, Joan M. Boylan and Jennifer A. Sanders
Pages 1050 - 1058
http://dx.doi.org/10.4161/cc.10.7.15230
Abstract | PDF

Rapamycin is an inhibitor of the mammalian Target of Rapamycin, mTOR, a nutrient-sensing signaling kinase and a key regulator of cell growth and proliferation. While rapamycin and related compounds have anti-tumor activity, a prevalent characteristic of cancer cells is resistance to their anti-proliferative effects. Our studies on nutrient regulation of fetal development showed that hepatocyte proliferation in the late gestation fetal rat is resistant to rapamycin. Extension of these studies to other tissues in the fetal and neonatal rat indicated that rapamycin resistance is a characteristic of normal cell proliferation in the growing organism. In hepatic cells, ribosomal biogenesis and cap-dependent protein translation were found to be relatively insensitive to the drug even though mTOR signaling was highly sensitive. Cell cycle progression was also resistant at the level of cyclin E-dependent kinase activity. Studies on the effect of rapamycin on gene expression in vitro and in vivo demonstrated that mTOR-mediated regulation of gene expression is independent of effects on cell proliferation and cannot be accounted for by functional regulation of identifiable transcription factors. Genes involved in cell metabolism were overrepresented among rapamycin-sensitive genes. We conclude that normal cellular proliferation in the context of a developing organism can be independent of mTOR signaling, that cyclin E-containing complexes are a critical locus for rapamycin sensitivity, and that mTOR functions as a modulator of metabolic gene expression in cells that are resistant to the anti-proliferative effects of the drug.

Open Access Article

Beyond knockout rats: New insights into finer genome manipulation in rats

Guanyi Huang, Chang Tong, Dhruv S. Kumbhani, Charles Ashton, Hexin Yan and Qi-Long Ying
Pages 1059 - 1066
http://dx.doi.org/10.4161/cc.10.7.15233
Abstract | PDF

The ability to “knockout” specific genes in mice via embryonic stem (ES) cell-based gene-targeting technology has significantly enriched our understanding of gene function in normal and disease phenotypes. Improvements on this original strategy have been developed to enable the manipulation of genomes in a more sophisticated fashion with unprecedented precision. The rat is the model of choice in many areas of scientific investigation despite the lack of rat genetic toolboxes. Most Recent advances of zinc finger nucleases (ZFNs) and rat ES cells are diminishing the gap between rat and mouse with respect to reverse genetic approaches. Importantly, the establishment of rat ES cell-based gene targeting technology, in combination with the unique advantages of using rats, provides new, exciting opportunities to create animal models that mimic human diseases more faithfully. We hereby report our recent results concerning finer genetic modifications in the rat, and propose their potential applications in addressing biological questions.

Open Access Article

Silencing FLIP_L modifies TNF-induced apoptotic protein expression

Lyubov Zaitseva, Stuart A. Rushworth and David J. MacEwan
Pages 1067 - 1072
http://dx.doi.org/10.4161/cc.10.7.15247
Abstract | PDF

Death-receptor induced apoptosis is regulated by FLIP [FLICE (Fas-associated protein with death domain-like IL-1β-converting enzyme)-inhibitory protein] via modification of caspase-8 activation. As an important modulator of apoptosis, the long isoform, FLIP_L, regulates life and death in many various types of normal and tumor cells and tissues to render resistance to death receptor-mediated apoptosis. In addition, FLIP_L has been shown to be involved in regulation of intrinsic (mitochondrial) pathways of apoptosis as well as regulating other proteins involved in cytoprotection and cell cycle progression. Therefore, understanding the role of FLIP_L in complex regulatory networks of cell survival/death mechanisms is vital for future developments to control diseases such as cancer. Here, we shown that silencing FLIP_L in HEK 293 cells changed the expression levels of proteins that are involved in both extrinsic and intrinsic apoptosis, as well as regulating tumor necrosis factor-α (TNF)-mediated apoptotic patterns. We also show that FLIP_L-silenced cells have a lower rate of proliferation and cell cycle progression when compared to control cells. Moreover, treatment with TNF restored proliferation rates in FLIP_L-silenced cells back to more normal levels when compared to control cells. These results suggest that cells have evolved complex compensatory mechanisms to overcome the absence of a key apoptotic regulatory proteins.




PERSPECTIVE

Open Access Article

Damage-induced localized hypermutability

Lauranell H. Burch, Yong Yang, Joan F. Sterling, Steven A. Roberts, Frank G. Chao, Hong Xu, Leilei Zhang, Jesse Walsh, Michael A. Resnick, Piotr A. Mieczkowski and Dmitry A. Gordenin
Pages 1073 - 1085
http://dx.doi.org/10.4161/cc.10.7.15319
Abstract | PDF


Genome instability continuously presents perils of cancer, genetic disease and death of a cell or an organism. At the same time, it provides for genome plasticity that is essential for development and evolution. We address here the genome instability confined to a small fraction of DNA adjacent to free DNA ends at uncapped telomeres and double-strand breaks. We found that budding yeast cells can tolerate nearly 20 kilobase regions of subtelomeric single-strand DNA that contain multiple UV-damaged nucleotides. During restoration to the double-strand state, multiple mutations are generated by error-prone translesion synthesis. Genome-wide sequencing demonstrated that multiple regions of damage-induced localized hypermutability can be tolerated, which leads to the simultaneous appearance of multiple mutation clusters in the genomes of UV- irradiated cells. High multiplicity and density of mutations suggest that this novel form of genome instability may play significant roles in generating new alleles for evolutionary selection as well as in the incidence of cancer and genetic disease.




REVIEW

Open Access Article

Heterotrimeric G protein signaling in cancer cells with regard to metastasis formation

Frank Entschladen, Kurt S. Zänker and Desmond G. Powe
Pages 1086 - 1091
http://dx.doi.org/10.4161/cc.10.7.15208
Abstract | PDF

The signal transduction mediated by heterotrimeric G proteins is involved in the regulation of a plethora of cell functions ranging from the sensation of light, taste and odor to chemotaxis, inflammation and the coordination of immune responses. These reactions have in common that they occur fast and are short-lived. Apart from this, it becomes increasingly evident, that the signaling of heterotrimeric G proteins has an imminent function in gene regulation, too, and therefore mediates even long-term effects. Herein, we illustrate the pathways of the four classes of α subunits and of the βγ subunits of these heterotrimeric G proteins especially with regard to their function in cancer. G protein signaling is crucial for the development and localization of metastases and furthermore has been shown to be involved in tumor growth and angiogenesis. We summarize the current knowledge, how these processes are regulated by the short-term cellular response and the long-term gene regulation in cancer cells, and we discuss possible strategies for a therapeutic intervention.




REPORTS

Open Access Article

Identification of Mom12 and Mom13, two novel modifier loci of Apc^Min-mediated intestinal tumorigenesis

Richard C. Crist, Jacquelyn J. Roth, Michael P. Lisanti, Linda D. Siracusa and Arthur M. Buchberg
Pages 1092 - 1099
http://dx.doi.org/10.4161/cc.10.7.15089
Abstract | PDF

Colorectal cancer is a heterogeneous disease resulting from a combination of genetic and environmental factors. The C57BL/6J (B6) Apc^Min/+ mouse develops polyps throughout the gastrointestinal tract and has been a valuable model for understanding the genetic basis of intestinal tumorigenesis. Apc^Min/+ mice have been used to study known oncogenes and tumor suppressor genes on a controlled genetic background. These studies often utilize congenic knockout alleles, which can carry an unknown amount of residual donor DNA. The Apc^Min model has also been used to identify modifer loci, known as Modifier of Min (Mom) loci, which alter Apc^Min-mediated intestinal tumorigenesis. B6 mice carrying a knockout allele generated in WW6 embryonic stem cells were crossed to B6 Apc^Min/+ mice to determine the effect on polyp multiplicity. The newly generated colony developed significantly more intestinal polyps than Apc^Min/+ controls. Polyp multiplicity did not correlate with inheritance of the knockout allele, suggesting the presence of one or more modifier loci segregating in the colony. Genotyping of simple sequence length polymorphism (SSLP) markers revealed residual 129X1/SvJ genomic DNA within the congenic region of the parental knockout line. An analysis of polyp multiplicity data and SSLP genotyping indicated the presence of two Mom loci in the colony: 1) Mom12, a dominant modifier linked to the congenic region on chromosome 6, and 2) Mom13, which is unlinked to the congenic region and whose effect is masked by Mom12. The identification of Mom12 and Mom13 demonstrates the potential problems resulting from residual heterozygosity present in congenic lines.

Open Access Article

MDM4 downregulates p53 transcriptional activity and response to stress during differentiation

Sergio Ménendez, Amanda M. Goh, Suzanne Camus, Kee Woei Ng, Nelly Kua, Vinay Badal and David P. Lane
Pages 1100 - 1108
http://dx.doi.org/10.4161/cc.10.7.15090
Abstract | PDF

Embryonic stem (ES) cells are invaluable for their therapeutic potential as well as for the study of early development. Their clinical use demands an understanding of ES cell differentiation, particularly with respect to cell proliferation and the maintenance of genomic integrity, processes for which the transcription factor p53 is essential. However, although the function of p53 as a tumor suppressor has been extensively studied, its role in ES cell biology has not been clearly elucidated. To study p53 activity and regulation in differentiating ES cells, we used knock-in constructs to create a novel reporter system that provides a direct readout of p53 transcriptional activity. We thereby determine that the p53 pathway is active in ES cells, but that p53 activity and the p53-dependent stress response decrease upon differentiation. Although p53 protein levels and activity are usually primarily controlled by the ubiquitin ligase MDM2, we identify the MDM2 homolog MDM4 as the key modulator of p53 activity in differentiating ES cells. Our results provide a better understanding of ES cell regulation and could help to optimize ES cell differentiation protocols for their use in regenerative medicine.

Open Access Article

The adult Drosophila gastric and stomach organs are maintained by a multipotent stem cell pool at the foregut/midgut junction in the cardia (proventriculus)

Shree Ram Singh, Xiankun Zeng, Zhiyu Zheng and Steven X. Hou
Pages 1109 - 1120
http://dx.doi.org/10.4161/cc.10.7.14830
Abstract | PDF

Stomach cancer is the second most frequent cause of cancer-related death worldwide. Thus, it is important to elucidate the properties of gastric stem cells, including their regulation and transformation. To date, such stem cells have not been identified in Drosophila. Here, using clonal analysis and molecular marker labeling, we identify a multipotent stem-cell pool at the foregut/midgut junction in the cardia (proventriculus). We found that daughter cells migrate upward either to anterior midgut or downward to esophagus and crop. The cardia functions as a gastric valve and the anterior midgut and crop together function as a stomach in Drosophila; therefore, we named the foregut/midgut stem cells as gastric stem cells (GaSC). We further found that JAK-STAT signaling regulates GaSCs’ proliferation, Wingless signaling regulates GaSCs’ self-renewal, and hedgehog signaling regulates GaSCs’ differentiation. The differentiation pattern and genetic control of the Drosophila GaSCs suggest the possible similarity to mouse gastric stem cells. The identification of the multipotent stem cell pool in the gastric gland in Drosophila will facilitate studies of gastric stem cell regulation and transformation in mammal.

Open Access Article

MiR-203 controls proliferation, migration and invasive potential of prostate cancer cell lines

Giuditta Viticchiè, Anna Maria Lena, Alessia Latina, Amanda Formosa, Lea H. Gregersen, Anders H. Lund, Sergio Bernardini, Alessandro Mauriello, Roberto Miano, Luigi G. Spagnoli, Richard A. Knight, Eleonora Candi and Gerry Melino
Pages 1121 - 1131
http://dx.doi.org/10.4161/cc.10.7.15180
Abstract | PDF

Prostate cancers show a slow progression from a local lesion (primary tumor) to a metastatic and hormone-resistant phenotype. After an initial step of hyperplasia, in a high percentage of cases a neoplastic transformation event occurs that, less frequently, is followed by epithelial to mesenchymal transition and invasion of healthy tissues (usually bones). MicroRNA-203 (miR-203) is a tumor suppressor microRNA often silenced in different malignancies. Here, we show that miR-203 is downregulated in clinical primary prostatic tumors compared to normal prostate tissue, and in metastatic prostate cancer cell lines compared to normal epithelial prostatic cells. Overexpression of miR-203 in brain or bone metastatic prostate cell lines (DU145 and PC3) is sufficient to induce a mesenchymal to epithelial transition with inhibition of cell proliferation, migration and invasiveness. We have identified CKAP2, LASP1, BIRC5, WASF1, ASAP1 and RUNX2 as new miR-203 direct target mRNAs involved in these events. Therefore, miR-203 could be a potentially new prognostic marker and therapeutic target in metastatic prostate cancer.

Open Access Article

Microarray analysis of the mammalian thromboxane receptor-Trypanosoma cruzi interaction

Herbert B. Tanowitz, Aparna Mukhopadhyay, Anthony W. Ashton, Michael P. Lisanti, Fabiana S. Machado, Louis M. Weiss and Shankar Mukherjee
Pages 1132 - 1143
http://dx.doi.org/10.4161/cc.10.7.15207
Abstract | PDF

Trypanosoma cruzi, the etiological agent of Chagas disease, causes vasculopathy and cardiomyopathy in humans and is associated with elevated levels of several vasoactive molecules such as nitric oxide, endothelin-1 and thromboxane A₂ (TXA₂). Parasite derived TXA₂ modulates vasculopathy and other pathophysiological features of Chagasic cardiomyopathy. Previously, we demonstrated that in response to infection with T. cruzi, TXA₂ receptor (TP) null mice displayed increased parasitemia; mortality and cardiac pathology compared with wild type (WT) and TXA₂ synthase null mice. In order to further study the role of TXA₂-TP signaling in the development of Chagas disease, GeneChip microarrays were used to detect transcriptome changes in rat fat pad endothelial cells (RFP-ECs) which is incapable of TXA₂ signaling (TP null) to that of control (wild type) and RFP-EC with reconstituted TP expression. Genes that were significantly regulated due to infection were identified using a time course of 2, 18 and 48 hrs post infection. We identified several key genes such as suppressor of cytokine signaling (SOCS-5), several cytokines (CSF-1, CXCF ligands), and MAP kinases (MAPK-1, Janus kinase) that were upregulated in the absence of TP signaling. These data underscore the importance of the interaction of the parasite with mammalian TP and may explain the increased mortality and cardiovascular pathology observed in infected TP null mice.

Open Access Article

Micro(mi)RNA expression profile of breast cancer epithelial cells treated with the anti-diabetic drug metformin: Induction of the tumor suppressor miRNA let-7a and suppression of the TGFβ-induced oncomiR miRNA-181a

Cristina Oliveras-Ferraros, Sílvia Cufí, Alejandro Vazquez-Martin, Violeta Zenobia Torres-Garcia, Sonia Del Barco, Begoña Martin-Castillo and Javier A. Menendez
Pages 1144 - 1151
http://dx.doi.org/10.4161/cc.10.7.15210
Abstract | PDF

An unexplored molecular scenario that might explain the inhibitory impact of the anti-diabetic drug metformin on the genesis of breast cancer relates to metformin’s ability to modulate the expression status of micro (mi)RNAs. We here report the first miRNA expression profiling of human epithelial breast cancer cells cultured in the presence of metformin. We conducted real-time transcription polymerase chain reaction (qRT-PCR) Arrays to quantitatively compare the expression profile of 88 cancer-related miRNA sequences before and after treatment of MCF-7 cells, which were used as well-differentiated, epithelioid cell controls, with graded concentrations of metformin. Metformin-treated MCF-7 cells notably exhibited up to 18-fold increases in miRNA lethal-7a (let-7a) expression compared with untreated control cells. We confirmed that MCF-7 cells undergoing epithelial-to-mesenchymal (EMT) transition in response to the cytokine TGFβ notably up-regulated (~5-fold) miRNA-181a expression and exhibited better mammosphere-forming capabilities. We then explored the ability of metformin to impede TGFβ-enhanced propensity of breast cancer stem cells to form mammospheres in a miRNA-181a-related manner. Remarkably, TGFβ treatment failed to up-regulate miRNA-181a expression in the presence of metformin, which was able to fully abrogate TGFβ-enhanced mammosphere-forming ability. In addition, metformin co-treatment fully prevented TGFβ-induced down-regulation of the tumor suppressor miRNA-96 (~10-fold). Metformin’s molecular functioning to prevent invasive breast cancer can be explained in terms of its previously unrecognized ability to efficiently up-regulate the tumor-suppressive miRNAs let-7a & miRNA-96 and inhibit the oncogenic miRNA-181a, thus epigenetically preserving the differentiated phenotype of mammary epithelium while preventing EMT-related cancer-initiating cell self-renewal.

Open Access Article

A minimally invasive assay for individual assessment of the ATM/CHEK2/p53 pathway activity

Sylwia Kabacik, Ana Ortega-Molina, Alejo Efeyan, Paul Finnon, Simon Bouffler, Manuel Serrano and Christophe Badie
Pages 1152 - 1161
http://dx.doi.org/10.4161/cc.10.7.15231
Abstract | PDF

Ionizing radiation induces DNA Double-Strand Breaks (DSBs) which activate the ATM/CHEK2/p53 pathway leading to cell cycle arrest and apoptosis through transcription of genes including CDKN1A (p21) and BBC3 (PUMA). This pathway prevents genomic instability and tumorigenesis as demonstrated in heritable syndromes [e.g. Ataxia Telangiectasia (AT); Li-Fraumeni syndrome (LFS)]. Here, a simple assay based on gene expression in peripheral blood to measure accurately ATM/CHEK2/p53 pathway activity is described. The expression of p21, Puma and Sesn2 was determined in blood from mice with different gene copy numbers of Atm, Trp53 (p53), Chek2 or Arf and in human blood and mitogen stimulated T-lymphocyte (MSTL) cultures from AT, AT carriers, LFS patients, and controls, both before and after ex vivo ionizing irradiation. Mouse Atm/Chek2/p53 activity was highly dependent on the copy number of each gene except Arf. In human MSTL, an AT case, AT carriers and LFS patients showed responses distinct from healthy donors. The relationship between gene copy number and transcriptional induction upon radiation was linear for p21 and Puma and correlated well with cancer incidence in p53 variant mice. This reliable blood test provides an assay to determine ATM/CHEK2/p53 pathway activity and demonstrates the feasibility of assessing the activity of this essential cancer protection pathway in simple assays. These findings may have implications for the individualized prediction of cancer susceptibility.

Open Access Article

The phenotype of MDM2 auto-degradation after DNA damage is due to epitope masking by phosphorylation

Qian Cheng and Jiandong Chen
Pages 1162 - 1166
http://dx.doi.org/10.4161/cc.10.7.15249
Abstract | PDF

It is widely accepted that DNA damage induces rapid degradation of MDM2 through phosphorylation, resulting in a transient reduction of MDM2 level. Elimination of MDM2 is a logical mechanism that stabilizes p53. This phenomenon has been reproduced by many independent studies and is frequently referenced. Here we present evidence that only phosphorylation-sensitive antibodies SMP14 and 2A10, but not other MDM2 antibodies, can detect robust down-regulation of MDM2 after DNA damage. Therefore, we conclude that DNA damage does not accelerate MDM2 auto-degradation. SMP14 and 2A10 are frequently used to detect human and mouse MDM2, respectively. While it is not clear whether the discrepancy is entirely due to the use of these antibodies, our results suggest that epitope masking by phosphorylation should be an important consideration when interpreting results of MDM2 analysis by SMP14 and 2A10.




RETRACTION

Open Access Article

Retracted Manuscript: The WNT-5a derived peptide, Foxy-5, possesses dual properties that impair progression of ERα negative breast cancer

Caroline E. Ford, Elin J. Ekström, Jillian Howlin and Tommy Andersson
Page 1167
http://dx.doi.org/10.4161/cc.10.7.15488
Abstract | PDF

Retraction for: “The WNT-5a derived peptide, Foxy-5, possesses dual properties that impair progression of ERa negative breast cancer,” by Caroline E. Ford, Elin J. Ekström, Jillian Howlin and Tommy Andersson, which appeared in the June 15, 2009 issue of Cell Cycle (Ford CE, et al. Cell Cycle 2009; 8:1838-1842; 10.4161/cc.8.12.8863). The authors wish to note the following: “Recently a paper, on which I was the senior author and that was published in the Proceedings of the National Academy of Sciences titled “Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor-negative breast cancer cells” (Ford CE, Ekström EJ, Andersson T. Proc Natl Acad Sci USA 2009; 106:3919-24) was retracted. The fact that this paper was the direct reason for our review article in the Cell Cycle journal makes it logical that I also retract the cited review article published in the Cell Cycle journal, the other authors approve this retraction. We apologize for any inconvenience this may have caused.”