1538-4101 2002212522 101137841 Cell Cycle cc Austin, Tx Landes Bioscience biweekly January 2002 - http://dx.doi.org/10.4161/cc http://www.landesbioscience.com/journals/cc/ 1538-4101 David Kachaner Pierre Génin Emmanuel Laplantine and Robert Weil cc Toward an integrative view of Optineurin functions Landes Bioscience 2012-08-01 2808 - 2818 Cell Cycle 11-15 Landes Bioscience This review highlights recent advances in our understanding of the mechanisms of Optineurin (Optn) action and its implication in diseases. Optn has emerged as a key player regulating various physiological processes, including membrane trafficking, protein secretion, cell division and host defense against pathogens. Furthermore, there is growing evidence for an association of Optn mutations with human diseases such as primary open-angle glaucoma, amyotrophic lateral sclerosis and Paget’s disease of bone. Optn functions depend on its precise subcellular localization and its interaction with other proteins. Here, we review the mechanisms that allow Optn to ensure a timely and spatially coordinated integration of different physiological processes and discuss how their deregulation may lead to different pathologies. http://dx.doi.org/10.4161/cc.20946 http://www.landesbioscience.com/journals/cc/article/20946/ article Review 1538-4101 Javier A. Menendez Cristina Oliveras-Ferraros Sílvia Cufí Bruna Corominas-Faja Jorge Joven Begoña Martin-Castillo and Alejandro Vazquez-Martin cc Metformin is synthetically lethal with glucose withdrawal in cancer cells Landes Bioscience 2012-08-01 2782 - 2792 Cell Cycle 11-15 Landes Bioscience Glucose deprivation is a distinctive feature of the tumor microecosystem caused by the imbalance between poor supply and an extraordinarily high consumption rate. The metabolic reprogramming from mitochondrial respiration to aerobic glycolysis in cancer cells (the “Warburg effect”) is linked to oncogenic transformation in a manner that frequently implies the inactivation of metabolic checkpoints such as the energy rheostat AMP-activated protein kinase (AMPK). Because the concept of synthetic lethality in oncology can be applied not only to genetic and epigenetic intrinsic differences between normal and cancer cells but also to extrinsic ones such as altered microenvironment, we recently hypothesized that stress-energy mimickers such as the AMPK agonist metformin should produce metabolic synthetic lethality in a glucose-starved cell culture milieu imitating the adverse tumor growth conditions in vivo. Under standard high-glucose conditions, metformin supplementation mostly caused cell cycle arrest without signs of apoptotic cell death. Under glucose withdrawal stress, metformin supplementation circumvented the ability of oncogenes (e.g., HER2) to protect breast cancer cells from glucose-deprivation apoptosis. Significantly, representative cell models of breast cancer heterogeneity underwent massive apoptosis (by > 90% in some cases) when glucose-starved cell cultures were supplemented with metformin. Our current findings may uncover crucial issues regarding the cell-autonomous metformin’s anti-cancer actions: (1) The offently claimed clinically irrelevant, non-physiological concentrations needed to observe the metformin’s anti-cancer effects in vitro merely underlie the artifactual interference of erroneous glucose-rich experimental conditions that poorly reflect glucose-starved in vivo conditions; (2) the preferential killing of cancer stem cells (CSC) by metformin may simply expose the best-case scenario for its synthetically lethal activity because an increased dependency on Warburg-like aerobic glycolysis (hyperglycolytic phenotype) is critical to sustain CSC stemness and immortality; (3) the microenvironment-mediated contextual synthetic lethality of metformin should be expected to enormously potentiate the anti-cancer effect of anti-angiogenesis agents that promote severe oxygen and glucose deprivation in certain areas of the tumor tissues. http://dx.doi.org/10.4161/cc.20948 http://www.landesbioscience.com/journals/cc/article/20948/ article Extra Views 1538-4101 Hoi Leong Xavier Wong Renhai Cao Guoxiang Jin Kui Ming Chan Yihai Cao and Zhongjun Zhou cc When MT1-MMP meets ADAMs Landes Bioscience 2012-08-01 2793 - 2798 Cell Cycle 11-15 Landes Bioscience MT1-MMP is a membrane-tethered enzyme capable of remodeling extracellular matrix. MT1-MMP-deficient mice exhibit systematic defects during development, especially in craniofacial development characterized by retarded calvarial bone formation. Recently, we identified MT1-MMP as a critical positive modulator of FGF signaling during intramembranous ossification. MT1-MMP cleaves ADAM9 to protect FGFR2 from ectodomain shedding. Depletion of ADAM9 in MT1-MMP-deficient mice significantly rescued the calvarial defects via restoring FGF signaling. Interestingly, this regulatory mechanism seems to be highly tissue-specific, as defective FGF2-induced corneal angiogenesis in Mmp14−/− mice could not be rescued by removal of ADAM9. In addition, MT1-MMP also cleaves another ADAM family member, ADAM15. Our current findings not only present a novel regulatory mechanism for FGF signaling but also reveal a functional crosstalk between MMP and ADAM families. Better understanding of the interplay between ADAMs and MT1-MMP and its consequences for signaling pathways will provide new insights into therapeutic approaches for the management of developmental disorders and various diseases, such as cancer. http://dx.doi.org/10.4161/cc.20949 http://www.landesbioscience.com/journals/cc/article/20949/ article Extra Views 1538-4101 Gennady Kholodii Olga Dantsevich and Vyacheslav Tarantul cc Transfecting DNA is frequently inserted near DNA replication origins Landes Bioscience 2012-08-01 2956 - 2958 Cell Cycle 11-15 Landes Bioscience http://dx.doi.org/10.4161/cc.20950 http://www.landesbioscience.com/journals/cc/article/20950/ article Letter to the Editor 1538-4101 Ranmal A. Samarasinghe Selma F. Witchell and Donald B. DeFranco cc Cooperativity and complementarity: Synergies in non-classical and classical glucocorticoid signaling Landes Bioscience 2012-08-01 2819 - 2827 Cell Cycle 11-15 Landes Bioscience Glucocorticoids (GCs) are an ubiquitous class of steroid hormones that exert a wide array of physiological effects. Traditionally, GC action has been considered to primarily involve transcriptional effects following the binding of hormone to the glucocorticoid receptor (GR) and subsequent activation or repression of target genes. However, a number of findings suggest that cellular responses following GC exposure may be mediated by transcription-independent, or “non-classical,” mechanisms. We have added to this growing body of work by recently uncovering a novel GC signaling pathway that operates through plasma membrane GRs to limit gap junction intercellular signaling and limit the proliferation of neural progenitor cells (NPCs). In this review, we highlight our current state of knowledge of non-classical GR signaling, in particular as it applies to neuronal function. Using NPCs as a cellular model, we speculate on the components of this non-classical pathway and the mechanisms whereby a number of cytoplasmic and nuclear signaling events may be integrated. http://dx.doi.org/10.4161/cc.21018 http://www.landesbioscience.com/journals/cc/article/21018/ article Review 1538-4101 Mir Farshid Alemdehy and Stefan J. Erkeland cc Stop the dicing in hematopoiesis: What have we learned? Landes Bioscience 2012-08-01 2799 - 2807 Cell Cycle 11-15 Landes Bioscience MicroRNAs (miRNAs) belong to an abundant class of highly conserved small (22nt) non-coding RNAs. MiRNA profiling studies indicate that their expression is highly cell type-dependent. DICER1 is an essential RNase III endoribonuclease for miRNA processing. Hematopoietic cell type- and developmental stage-specific Dicer1 deletion models show that miRNAs are essential regulators of cellular survival, differentiation and function. For instance, miRNA deficiency in hematopoietic stem cells and progenitors of different origins results in decreased cell survival, dramatic developmental aberrations or dysfunctions in mice. We recently found that homozygous Dicer1 deletion in myeloid-committed progenitors results in an aberrant expression of stem cell genes and induces a regained self-renewal capacity. Moreover, Dicer1 deletion causes a block in macrophage development and myeloid dysplasia, a cellular condition that may be considered as a preleukemic state. However, Dicer1-null cells do not develop leukemia in mice, indicating that depletion of miRNAs is not enough for tumorigenesis. Surprisingly, we found that heterozygous Dicer1 deletion in myeloid-committed progenitors, but not Dicer1 knockout, collaborates with p53 deletion in leukemic progression and results in various types of leukemia. Our data indicate that Dicer1 is a haploinsufficient tumorsuppressor in hematopoietic neoplasms, which is consistent with the observed downregulation of miRNA expression in human leukemia samples. Here, we review the various hematopoietic specific Dicer1 deletion mouse models and the phenotypes observed within the different hematopoietic lineages and cell developmental stages. Finally, we discuss the role for DICER1 in mouse and human malignant hematopoiesis. http://dx.doi.org/10.4161/cc.21077 http://www.landesbioscience.com/journals/cc/article/21077/ article Extra Views 1538-4101 So Young Park and Maki Asano cc An <italic>orc1</italic> allele with a mutated APC motif is female sterile with amplification defects Landes Bioscience 2012-08-01 2828 - 2832 Cell Cycle 11-15 Landes Bioscience The origin recognition complex 1 (ORC1) is the largest subunit of the ORC, the heteromeric hexamer. ORC1 is an essential component of the pre-replicative complex (pre-RC) that licenses eukaryote DNA replication origins. The levels of ORC1 fluctuate during the mitotic cell cycle in Drosophila as well as in some human cells. Proteolysis of ORC1 occurs at the end of M phase in Drosophila, which is mediated by the anaphase-promoting complex (APC), and in late S phase in human cells by Skip-Cullin-F box (SCF). Previously we showed that proteolysis of ORC1 by APC is mediated by the ORC1 destruction box (the O-box), an APC motif conserved among species yet distinct from the D-box or KEN-box. Recently we showed that replacing the O-box with the D-box (ORC1O→D) changes the degradation profile of ORC1 during a canonical cell cycle. Here we report further characterization of the ORC1O→D allele that turned out to be a useful tool to examine the function of ORC1 in other modes of DNA replication during oogenesis. In endoreplication stages ORC1O→D does not change any DNA content profiles, consistent with our previous finding that ORC is dispensable for endoreplication. However, in amplification stage replication efficiency of ORC1O→D is drastically reduced, which resulted in amplification defects that led to thin egg shell phenotype. Taken together, our analyses show that orc1 allele newly identified is female sterile and possesses a unique feature of phenotypes that are distinct in different modes of DNA replication. http://dx.doi.org/10.4161/cc.21168 http://www.landesbioscience.com/journals/cc/article/21168/ article Report 1538-4101 Meng Xia Hui He Ying Wang Minxi Liu Tao Zhou Min Lin Zuomin Zhou Ran Huo Qi Zhou and Jiahao Sha cc PCBP1 is required for maintenance of the transcriptionally silent state in fully grown mouse oocytes Landes Bioscience 2012-08-01 2833 - 2842 Cell Cycle 11-15 Landes Bioscience Global transcriptional silencing in fully grown oocytes is a critical event during mammalian oogenesis. However, how this event is regulated remains elusive. Here, we provide evidence that poly(rC)-binding protein 1 (PCBP1), a protein found by us previously to be present in metaphase II (MII) mouse oocytes, participates in maintenance of the transcriptionally silent state in fully grown mouse oocytes. Knocking down Pcbp1 by microinjection of its specific siRNAs into fully grown germinal vesicle (GV) oocytes resulted in remarkable changes in their transcriptional state, including the disequilibrium between the number of oocytes with an NSN (non-surrounded nucleolus) and those with a SN (surrounded nucleolus), and obvious transcriptional reactiviation in oocytes with a SN configuration as evidenced by BrUTP incorporation assay and immunofluorescent labeling of phosphorylated RNA polymerase II CTD and trimethylated H3 lysine 4, markers for active transcription. Furthermore, in a comprehensive microarray analysis of the preovulatory oocyte transcriptome, an incredible number of nearly 4,000 transcripts were upregulated in the Pcbp1 knockdown groups. These data indicate that lack of the function of PCBP1 disrupts the quiescent status of transcription in the fully grown oocytes, and hence supporting a role of this protein in the regulation of global transcriptional silcencing in fully grown mouse oocytes. http://dx.doi.org/10.4161/cc.21169 http://www.landesbioscience.com/journals/cc/article/21169/ article Report 1538-4101 Alexandra Menant and Roger E. Karess cc Inducing “cytokinesis” without mitosis in unfertilized Drosophila eggs Landes Bioscience 2012-08-01 2856 - 2863 Cell Cycle 11-15 Landes Bioscience Selection of the cleavage plane during cytokinesis in dividing cells is linked to the position of the mitotic spindle. A major player in cleavage plane positioning is believed to be the anaphase central spindle and its associated signaling complex called centralspindlin, composed of MgcRacGap and MKLP1. Centralspindlin has the capacity to induce furrowing of the cell cortex by promoting the localized activation of RhoA, which in turn promotes assembly of the contractile ring. We have found a way to induce a cytokinesis-like process in unfertilized Drosophila eggs and very early embryos, when spindle structures are few and located far from invaginating egg cortex. The simple injection of a small molecule inhibitor of Cdk1/Cyclin B (either Roscovitin or RO3306) is sufficient to promote membrane invagination near the site of injection. The furrow generated is in many respects similar to a classical cleavage furrow. Actin, myosin, anillin and MKLP1 are all associated with the forming furrow, which in some cases can entirely circumscribe the unfertilized egg. A similar furrow can also be generated by the localized injection of constitutively active RhoA protein, suggesting that Cdk1 is normally an upstream inhibitor of RhoA activation. We show further that this process apparently is not associated with microtubules. Since simple localized inhibition of Cdk1 is sufficient to induce a furrow, we suggest that in real cytokinesis in normal cells, the localized downregulation of Cdk1 activity at the metaphase-anaphase transition may contribute, along with the spindle, to the positioning of the cleavage furrow. http://dx.doi.org/10.4161/cc.21190 http://www.landesbioscience.com/journals/cc/article/21190/ article Report 1538-4101 Melchiorre Cervello Dimcho Bachvarov Nadia Lampiasi Antonella Cusimano Antonina Azzolina James A. McCubrey and Giuseppe Montalto cc Molecular mechanisms of sorafenib action in liver cancer cells Landes Bioscience 2012-08-01 2843 - 2855 Cell Cycle 11-15 Landes Bioscience Sorafenib, a multikinase inhibitor, recently received FDA approval for the treatment of advanced hepatocellular carcinoma (HCC). However, as the clinical application of sorafenib evolves, there is increasing interest in defining the mechanisms underlying its anti-tumor activity. Considering that this specific inhibitor could target unexpected molecules depending on the biologic context, a precise understanding of its mechanism of action could be critical to maximize its treatment efficacy, while minimizing adverse effects. Two human HCC cell lines (HepG2 and Huh7), carrying different biological and genetic characteristics, were used in this study to examine the intracellular events leading to sorafenib-induced HCC cell-growth inhibition. Sorafenib inhibited cell growth in both cell lines in a dose- and time-dependent manner and significantly altered expression levels of 826 and 2011 transcripts in HepG2 and Huh7 cells, respectively. Genes functionally involved in angiogenesis, apoptosis, transcription regulation, signal transduction, protein biosynthesis and modification were predominantly upregulated, while genes implicated in cell cycle control, DNA replication recombination and repair, cell adhesion, metabolism and transport were mainly downregulated upon treatment. However, each sorafenib-treated HCC cell line displayed specificity in the expression and activity of crucial factors involved in hepatocarcinogenesis. The altered expression of some of these genes was confirmed by semiquantitative and quantitative RT-PCR and by western blotting. Many novel genes emerged from our transcriptomics analysis that had not previously been reported to be effected by sorafenib. Further functional analyses may determine whether these genes can serve as potential molecular targets for more effective anti-HCC strategies. http://dx.doi.org/10.4161/cc.21193 http://www.landesbioscience.com/journals/cc/article/21193/ article Report 1538-4101 Lei Lv Tianwei Zhang Qiyi Yi Yun Huang Zheng Wang Heli Hou Huan Zhang Wei Zheng Qiaomei Hao Zongyou Guo Howard J. Cooke and Qinghua Shi cc Tetraploid cells from cytokinesis failure induce aneuploidy and spontaneous transformation of mouse ovarian surface epithelial cells Landes Bioscience 2012-08-01 2864 - 2875 Cell Cycle 11-15 Landes Bioscience Most ovarian cancers originate from the ovarian surface epithelium and are characterized by aneuploid karyotypes. Aneuploidy, a consequence of chromosome instability, is an early event during the development of ovarian cancers. However, how aneuploid cells are evolved from normal diploid cells in ovarian cancers remains unknown. In the present study, cytogenetic analyses of a mouse syngeneic ovarian cancer model revealed that diploid mouse ovarian surface epithelial cells (MOSECs) experienced an intermediate tetraploid cell stage, before evolving to aneuploid (mainly near-tetraploid) cells. Using long-term live-cell imaging followed by fluorescence in situ hybridization (FISH), we demonstrated that tetraploid cells originally arose from cytokinesis failure of bipolar mitosis in diploid cells, and gave rise to aneuploid cells through chromosome mis-segregation during both bipolar and multipolar mitoses. Injection of the late passage aneuploid MOSECs resulted in tumor formation in C57BL/6 mice. Therefore, we reveal a pathway for the evolution of diploid to aneuploid MOSECs and elucidate a mechanism for the development of near-tetraploid ovarian cancer cells. http://dx.doi.org/10.4161/cc.21196 http://www.landesbioscience.com/journals/cc/article/21196/ article Report 1538-4101 Deepak Adhikari Kui Liu and Yan Shen cc Cdk1 drives meiosis and mitosis through two different mechanisms Landes Bioscience 2012-08-01 2763 - 2764 Cell Cycle 11-15 Landes Bioscience Comment on: Adhikari D, et al. Hum Mol Gene 2012; 21:2476-84. http://dx.doi.org/10.4161/cc.21254 http://www.landesbioscience.com/journals/cc/article/21254/ article Editorials: Cell Cycle Features 1538-4101 Andrea Frontini Antonio Giordano and Saverio Cinti cc Endothelial cells of adipose tissues: A niche of adipogenesis Landes Bioscience 2012-08-01 2765 - 2766 Cell Cycle 11-15 Landes Bioscience Comment on: Tran KV, et al. Cell Metab 2012; 15:222-9. http://dx.doi.org/10.4161/cc.21255 http://www.landesbioscience.com/journals/cc/article/21255/ article Editorials: Cell Cycle Features 1538-4101 Vivian W.Y. Wong and Kim B. Jensen cc Environmental stimuli and intestinal stem cell behavior Landes Bioscience 2012-08-01 2767 - 2768 Cell Cycle 11-15 Landes Bioscience Comment on: Wong VWY, et al. Nat Cell Biol 2012; 14:401-8. http://dx.doi.org/10.4161/cc.21256 http://www.landesbioscience.com/journals/cc/article/21256/ article Editorials: Cell Cycle Features 1538-4101 Ian M. Willis and Jaehoon Lee cc Two new kinases in the TOR signaling network regulate ribosome and tRNA synthesis Landes Bioscience 2012-08-01 2769 - 2770 Cell Cycle 11-15 Landes Bioscience Comment on: Lee J, et al. Mol Cell 2012; 45:836-43. http://dx.doi.org/10.4161/cc.21257 http://www.landesbioscience.com/journals/cc/article/21257/ article Editorials: Cell Cycle Features 1538-4101 Wiebke Chemnitz Galal Young-Hoon Kang and Jerard Hurwitz cc Establishing the human rolling circle reaction Landes Bioscience 2012-08-01 2771 - 2772 Cell Cycle 11-15 Landes Bioscience Comment on: Kang YH, et al. Proc Natl Acad Sci USA 2012; 109:6042-7. http://dx.doi.org/10.4161/cc.21258 http://www.landesbioscience.com/journals/cc/article/21258/ article Editorials: Cell Cycle Features 1538-4101 Gray F. Crouse cc Mismatch repair outside of replication Landes Bioscience 2012-08-01 2773 - 2774 Cell Cycle 11-15 Landes Bioscience Comment on: Rodriguez GP, et al. Proc Natl Acad Sci USA 2012; 109:6153-8. http://dx.doi.org/10.4161/cc.21259 http://www.landesbioscience.com/journals/cc/article/21259/ article Editorials: Cell Cycle Features 1538-4101 Bethann N. Johnson Rakshita A. Charan and Matthew J. LaVoie cc Recognizing the cooperative and independent mitochondrial functions of Parkin and PINK1 Landes Bioscience 2012-08-01 2775 - 2776 Cell Cycle 11-15 Landes Bioscience Comment on: Johnson BN, et al. Proc Natl Acad Sci USA 2012; 109:6283-8. http://dx.doi.org/10.4161/cc.21261 http://www.landesbioscience.com/journals/cc/article/21261/ article Editorials: Cell Cycle Features 1538-4101 Tak-hong Cheung Kwun-nok Mimi Man Mei-yung Yu So-fan Yim Nelson S.S. Siu Keith W.K. Lo Graeme Doran Raymond R.Y. Wong Vivian W. Wang David I. Smith Michael J. Worley Jr. Ross S. Berkowitz Tony K.H. Chung and Yick-fu Wong cc Dysregulated microRNAs in the pathogenesis and progression of cervical neoplasm Landes Bioscience 2012-08-01 2876 - 2884 Cell Cycle 11-15 Landes Bioscience MicroRNAs (miRNAs) play an important role in a variety of physiological as well as pathophysiological processes, including carcinogenesis. The aim of this study is to identify a distinct miRNA expression signature for cervical intraepithelial neoplasia (CIN) and to unveil individual miRNAs that may be involved in the development of cervical carcinoma. Expression profiling using quantitative real-time RT-PCR of 202 miRNAs was performed on micro-dissected high-grade CIN (CIN 2/3) tissues and compared to normal cervical epithelium. Unsupervised hierarchical clustering of the miRNA expression pattern displayed a distinct separation between the CIN and normal cervical epithelium samples. Supervised analysis identified 12 highly differentially regulated miRNAs, including miR-518a, miR-34b, miR-34c, miR-20b, miR-338, miR-9, miR-512-5p, miR-424, miR-345, miR-10a, miR-193b and miR-203, which distinguished the high-grade CIN specimens from normal cervical epithelium. This miRNA signature was further validated by an independent set of high-grade CIN cases. The same characteristic signature can also be used to distinguish cervical squamous cell carcinoma from normal controls. Target prediction analysis revealed that these dysregulated miRNAs mainly control apoptosis signaling pathways and cell cycle regulation. These findings contribute to understanding the role of microRNAs in the pathogenesis and progression of cervical neoplasm at the molecular level. http://dx.doi.org/10.4161/cc.21278 http://www.landesbioscience.com/journals/cc/article/21278/ article Report 1538-4101 Jennifer Chea Sufang Zhang Hong Zhao Zhongtao Zhang Ernest Y.C. Lee Zbigniew Darzynkiewicz and Marietta Y.W.T. Lee cc Spatiotemporal recruitment of human DNA polymerase delta to sites of UV damage Landes Bioscience 2012-08-01 2885 - 2895 Cell Cycle 11-15 Landes Bioscience Human DNA polymerase δ (Pol δ) is involved in various DNA damage responses in addition to its central role in DNA replication. The Pol δ4 holoenzyme consists of four subunits, p125, p50, p68 and p12. It has been established that the p12 subunit is rapidly degraded in response to DNA damage by UV leading to the in vivo conversion of Pol δ4 to Pol δ3, a trimeric form lacking the p12 subunit. We provide the first analysis of the time-dependent recruitment of the individual Pol δ subunits to sites of DNA damage produced by UV irradiation through 5 μm polycarbonate filters by immunofluorescence microscopy and laser scanning cytometry (LSC). Quantitative analysis demonstrates that the recruitments of the three large subunits was near complete by 2 h and did not change significantly up to 4 h after UV exposure. However, the recruitment of p12 was incomplete even at 4 h, with about 70% of the Pol δ lacking the p12 subunit. ChIP analysis of Pol δ after global UV irradiation further demonstrates that only p125, p50 and p68 were present. Thus, Pol δ3 is the predominant form of Pol δ at sites of UV damage as a result of p12 degradation. Using LSC, we have further confirmed that Pol δ was recruited to CPD damage sites in all phases of the cell cycle. Collectively, our results show that Pol δ at the DNA damage site is the Pol δ trimer lacking p12 regardless of the cell cycle phase. http://dx.doi.org/10.4161/cc.21280 http://www.landesbioscience.com/journals/cc/article/21280/ article Report 1538-4101 Jenn Hui Khong Tao Zhang Jayantha Gunaratne Walter Blackstock and Uttam Surana cc “Reductional anaphase” in replication-defective cells is caused by ubiquitin-conjugating enzyme Cdc34-mediated deregulation of the spindle Landes Bioscience 2012-08-01 2896 - 2910 Cell Cycle 11-15 Landes Bioscience Equal partitioning of the duplicated chromosomes into two daughter cells during cell division is a coordinated process and is initiated only after completion of DNA synthesis. However, this strict order of execution breaks down in CDC6-deficient cells. Cdc6, an evolutionarily conserved protein, is required for the assembly of pre-replicative complexes (pre-RCs) and is essential for the initiation of DNA replication. Yeast cells lacking Cdc6 function, though unable to initiate DNA replication, proceed to undergo “reductional anaphase” by partitioning the unreplicated chromosomes and lose viability rapidly. This extreme form of genomic instability in cdc6 cells is thought to be due to inactivation of a pre-RC based, Cdc6-dependent checkpoint mechanism that, during normal cell cycle, inhibits premature onset of mitosis until pre-RC is assembled. Here, we show that chromosome segregation in cdc6 mutant is caused not by precocious initiation of mitosis in the absence of a checkpoint, but by the deregulation of spindle dynamics induced via a regulatory network involving the ubiquitin-conjugating enzyme Cdc34, microtubule-associated proteins (MAPs) and the anaphase-promoting complex (APC) activator Cdh1. This regulatory circuit governs spindle behavior in the early part of the division cycle and precipitates catastrophic chromosome segregation in the absence of DNA replication. http://dx.doi.org/10.4161/cc.21303 http://www.landesbioscience.com/journals/cc/article/21303/ article Report 1538-4101 Carmela Guido Salvatore Panza Marta Santoro Paola Avena Maria Luisa Panno Ida Perrotta Francesca Giordano Ivan Casaburi Stefania Catalano Francesca De Amicis Federica Sotgia Michael P. Lisanti Sebastiano Andò and Saveria Aquila cc Estrogen receptor beta (ERβ) produces autophagy and necroptosis in human seminoma cell line through the binding of the Sp1 on the phosphatase and tensin homolog deleted from chromosome 10 (PTEN) promoter gene Landes Bioscience 2012-08-01 2911 - 2921 Cell Cycle 11-15 Landes Bioscience Testicular germ cell tumors are the most common tumor in male and the least studied. We focused on human seminoma using the TCAM2 cell line. Through ERβ, 10 nM estradiol (E2) was able to induce PTEN gene expression and promoter transactivation. Transient transfections, ChIP and EMSA assays evidenced the 5′-flanking region of PTEN gene promoter E2-responsive. The ERβ binding to the Sp1 on PTEN promoter decreased cell survival. The presence of ERβ or PTEN is necessary to induce the loss of cell survival upon E2, addressing their cooperation in this action. pAKT and AKT expression decreased under E2 and DPN, while known apoptotic markers appeared to be unchanged. The PI3K/AKT pathway inhibition also leads to autophagy: E2 and DPN enhanced the expression of autophagy-related markers such as PI3III, Beclin 1, AMBRA and UVRAG. MDC and TEM assays confirmed E2-induced autophagy. The absence of DNA fragmentation, caspase 9 and PARP1 cleavages suggested that necroptosis and/or parthanatos may occur. FACS analysis, LDH assay and RIP1 expression attested this hypothesis. Our study reveals a unique mechanism through which ERβ/PTEN signaling induces cell death in TCAM2 by autophagy and necroptosis. These data, supporting estrogen-dependency of human seminoma, propose ERβ ligands for therapeutic use in the treatment of this pathological condition. http://dx.doi.org/10.4161/cc.21336 http://www.landesbioscience.com/journals/cc/article/21336/ article Report 1538-4101 Nuo Yang Carl D. Morrison Peijun Liu Jeff Miecznikowski Wiam Bshara Suxia Han Qing Zhu Angela R. Omilian Xu Li and Jianmin Zhang cc TAZ induces growth factor-independent proliferation through activation of EGFR ligand amphiregulin Landes Bioscience 2012-08-01 2922 - 2930 Cell Cycle 11-15 Landes Bioscience The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. We previously showed that the pivotal effector of this pathway, YAP, is amplified in tumors and promotes epithelial-to-mesenchymal transition (EMT) and malignant transformation. Here, we report that overexpression of TAZ, a paralog of YAP, in human mammary epithelial cells promotes EMT and, in particular, some invasive structures in 3D cultures. TAZ also leads to cell migration and anchorage-independent growth in soft agar. Furthermore, we identified amphiregulin (AREG), an epidermal growth factor receptor (EGFR) ligand, as a target of TAZ. We show that AREG functions in a non-cell-autonomous manner to mediate EGF-independent growth and malignant behavior of mammary epithelial cells. In addition, ablation of TEAD binding completely abolishes the TAZ-induced phenotype. Last, analysis of breast cancer patient samples reveals a positive correlation between TAZ and AREG in vivo. In summary, TAZ-dependent secretion of AREG indicates that activation of the EGFR signaling is an important non-cell-autonomous effector of the Hippo pathway, and TAZ as well as its targets may play significant roles in breast tumorigenesis and metastasis. http://dx.doi.org/10.4161/cc.21386 http://www.landesbioscience.com/journals/cc/article/21386/ article Report 1538-4101 Pheruza Tarapore Kazuhiko Hanashiro and Kenji Fukasawa cc Analysis of centrosome localization of BRCA1 and its activity in suppressing centrosomal aster formation Landes Bioscience 2012-08-01 2931 - 2946 Cell Cycle 11-15 Landes Bioscience BRCA1, a product of a familial breast and ovarian cancer susceptibility gene, localizes to centrosomes and physically interacts with γ-tubulin, a key centrosomal protein for microtubule nucleation and anchoring at centrosomes. Here, we performed a rigorous analysis of centrosome localization of BRCA1, and found that BRCA1 is specifically associated with mother centrioles in unduplicated centrosomes, and daughter centrioles acquire BRCA1 prior to initiation of duplication, and thus duplicated centrosomes are both bound by BRCA1. We further found that BRCA1 suppresses centrosomal aster formation. In addition, we identified a new domain of BRCA1 critical for γ-tubulin binding, which confers not only its localization to centrosomes, but also its activity to suppress centrosomal aster formation. http://dx.doi.org/10.4161/cc.21396 http://www.landesbioscience.com/journals/cc/article/21396/ article Report 1538-4101 David A. Gillespie cc Short-circuiting the cell cycle for cancer therapy Landes Bioscience 2012-08-01 2777 - 2777 Cell Cycle 11-15 Landes Bioscience Comment on: Carrassa L, et al. Cell Cycle 2012; 2507-17. http://dx.doi.org/10.4161/cc.21392 http://www.landesbioscience.com/journals/cc/article/21392/ article Cell Cycle News & Views 1538-4101 Scott Tsuchiyama and Brian K. Kennedy cc Vacuolar dynamics and replicative aging Landes Bioscience 2012-08-01 2778 - 2778 Cell Cycle 11-15 Landes Bioscience Comment on: Gebre S, et al. Cell Cycle 2012; 11:2176-88. http://dx.doi.org/10.4161/cc.21393 http://www.landesbioscience.com/journals/cc/article/21393/ article Cell Cycle News & Views 1538-4101 Ashwani Khurana and Viji Shridhar cc Metformin is synthetically lethal with glucose withdrawal in cancer cells Landes Bioscience 2012-08-01 2779 - 2779 Cell Cycle 11-15 Landes Bioscience Comment on: Menendez JA, et al. Cell Cycle 2012; 11: 2782-92. http://dx.doi.org/10.4161/cc.21394 http://www.landesbioscience.com/journals/cc/article/21394/ article Cell Cycle News & Views 1538-4101 Fayaz Malik Hasan Korkaya Shawn G. Clouthier and Max S. Wicha cc Lin28 and HER2: Two stem cell regulators conspire to drive aggressive breast cancer Landes Bioscience 2012-08-01 2780 - 2781 Cell Cycle 11-15 Landes Bioscience Comment on: Feng CN, et al. Cell Cycle 2012; 11:2486-94. http://dx.doi.org/10.4161/cc.21395 http://www.landesbioscience.com/journals/cc/article/21395/ article Cell Cycle News & Views 1538-4101 Jayabal Panneerselvam Hwan Ki Park Jun Zhang Fred Duafalia Dudimah Piyan Zhang Hong Wang and Peiwen Fei cc FAVL impairment of the Fanconi anemia pathway promotes the development of human bladder cancer Landes Bioscience 2012-08-01 2947 - 2955 Cell Cycle 11-15 Landes Bioscience Effectiveness of DNA cross-linking drugs in the treatment of bladder cancer suggests that bladder cancer cells may have harbored an insufficient cellular response to DNA cross-link damage, which will sensitize cells to DNA cross-linking agents. Cell sensitivity benefits from deficient DNA damage responses, which, on the other hand, can cause cancer. Many changed cellular signaling pathways are known to be involved in bladder tumorigenesis; however, DNA cross-link damage response pathway [Fanconi anemia (FA) pathway], whose alterations appear to be a plausible cause of the development of bladder cancer, remains an under-investigated area in bladder cancer research. In this study, we found FAVL (variant of FA protein L—FANCL) was elevated substantially in bladder cancer tissues examined. Ectopic expression of FAVL in bladder cancer cells as well as normal human cells confer an impaired FA pathway and hypersensitivity to Mitomycin C, similar to those found in FA cells, indicating that FAVL elevation may possess the same tumor promotion potential as an impaired FA pathway harbored in FA cells. Indeed, a higher level of FAVL expression can promote the growth of bladder cancer cells in vitro and in vivo, which, at least partly, results from FAVL perturbation of FANCL expression, an essential factor for the activation of the FA pathway. Moreover, a higher level of FAVL expression was found to be associated with chromosomal instability and the invasiveness of bladder cancer cells. Collectively, FAVL elevation can increase the tumorigenic potential of bladder cancer cells, including the invasive potential that confers the development of advanced bladder cancer. These results enhance our understanding the pathogenesis of human bladder cancer, holding a promise to develop additional effective tools to fight human bladder cancer. http://dx.doi.org/10.4161/cc.21400 http://www.landesbioscience.com/journals/cc/article/21400/ article Report