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 Petra Mikolcevic Johannes Rainer and Stephan Geley cc Orphan kinases turn eccentric: A new class of cyclin Y-activated, membrane-targeted CDKs Landes Bioscience 2012-10-15 3758 - 3768 Cell Cycle 11-20 Landes Bioscience PCTAIRE kinases (PCTK) are a highly conserved, but poorly characterized, subgroup of cyclin-dependent kinases (CDK). They are characterized by a conserved catalytic domain flanked by N- and C-terminal extensions that are involved in cyclin binding. Vertebrate genomes contain three highly similar PCTAIRE kinases (PCTK1,2,3, a.k.a., CDK16,17,18), which are most abundant in post-mitotic cells in brain and testis. Consistent with this restricted expression pattern, PCTK1 (CDK16) has recently been shown to be essential for spermatogenesis. PCTAIREs are activated by cyclin Y (CCNY), a highly conserved single cyclin fold protein. By binding to N-myristoylated CCNY, CDK16 is targeted to the plasma membrane. Unlike conventional cyclin-CDK interactions, binding of CCNY to CDK16 not only requires the catalytic domain, but also domains within the N-terminal extension. Interestingly, phosphorylation within this domain blocks CCNY binding, providing a novel means of cyclin-CDK regulation. By using these functional characteristics, we analyzed “PCTAIRE” sequence containing protein kinase genes in genomes of various organisms and found that CCNY and CCNY-dependent kinases are restricted to eumetazoa and possibly evolved along with development of a central nervous system. Here, we focus on the structure and regulation of PCTAIREs and discuss their established functions. http://dx.doi.org/10.4161/cc.21592 http://www.landesbioscience.com/journals/cc/article/21592/ article Review 1538-4101 William H. Conrad Reyna D. Swift Travis L. Biechele Rima M. Kulikauskas Randall T. Moon and Andy J. Chien cc Regulating the response to targeted MEK inhibition in melanoma: Enhancing apoptosis in NRAS- and BRAF-mutant melanoma cells with Wnt/β-catenin activation Landes Bioscience 2012-10-15 3724 - 3730 Cell Cycle 11-20 Landes Bioscience The limitations of revolutionary new mutation-specific inhibitors of BRAFV600E include the universal recurrence seen in melanoma patients treated with this novel class of drugs. Recently, our lab showed that simultaneous activation of the Wnt/β-catenin signaling pathway and targeted inhibition of BRAFV600E by PLX4720 synergistically induces apoptosis across a spectrum of BRAFV600E melanoma cell lines. As a follow-up to that study, treatment of BRAF-mutant and NRAS-mutant melanoma lines with WNT3A and the MEK inhibitor AZD6244 also induces apoptosis. The susceptibility of BRAF-mutant lines and NRAS-mutant lines to apoptosis correlates with negative regulation of Wnt/β-catenin signaling by ERK/MAPK signaling and dynamic decreases in abundance of the downstream scaffolding protein, AXIN1. Apoptosis-resistant NRAS-mutant lines can sensitize to AZD6244 by pretreatment with AXIN1 siRNA, similar to what we previously reported in BRAF-mutant cell lines. Taken together, these findings indicate that NRAS-mutant melanoma share with BRAF-mutant melanoma the potential to regulate apoptosis upon MEK inhibition through WNT3A and dynamic regulation of cellular AXIN1. Understanding the cellular context that makes melanoma cells susceptible to this combination treatment will contribute to the study and development of novel therapeutic combinations that may lead to more durable responses. http://dx.doi.org/10.4161/cc.21645 http://www.landesbioscience.com/journals/cc/article/21645/ article Extra Views 1538-4101 Nitin Raj Liang Zhang Yiliang Wei David N. Arnosti and R. William Henry cc Rbf1 degron dysfunction enhances cellular DNA replication Landes Bioscience 2012-10-15 3731 - 3738 Cell Cycle 11-20 Landes Bioscience The E2F family of transcription factors contributes to oncogenesis through activation of multiple genes involved in cellular proliferation, a process that is opposed by the Retinoblastoma tumor suppressor protein (RB). RB also increases E2F1 stability by inhibiting its proteasome-mediated degradation, but the consequences of this post-translational regulation of E2F1 remain unknown. To better understand the mechanism of E2F stabilization and its physiological relevance, we examined the streamlined Rbf1-dE2F1 network in Drosophila. During embryonic development, Rbf1 is insulated from ubiquitin-mediated turnover by the COP9 signalosome, a multi-protein complex that modulates E3 ubiquitin ligase activity. Here, we report that the COP9 signalosome also protects the Cullin4-E3 ligase that is responsible for dE2F1 proteasome-mediated destruction. This dual role of the COP9 signalosome may serve to buffer E2F levels, enhancing its turnover via Cul4 protection and its stabilization through protection of Rbf1. We further show that Rbf1-mediated stabilization of dE2F1 and repression of dE2F1 cell cycle-target genes are distinct properties. Removal of an evolutionarily conserved Rbf1 C terminal degron disabled Rbf1 repression without affecting dE2F1 stabilization. This mutant form of Rbf1 also enhanced G1-to-S phase progression when expressed in Rbf1-containing S2 embryonic cells, suggesting that such mutations may generate gain-of-function properties relevant to cellular transformation. Consistent with this idea, several studies have identified mutations in the homologous C terminal domains of RB and p130 in human cancer. http://dx.doi.org/10.4161/cc.21665 http://www.landesbioscience.com/journals/cc/article/21665/ article Extra Views 1538-4101 Peter J. McHugh Thomas A. Ward and Miroslav Chovanec cc A prototypical Fanconi anemia pathway in lower eukaryotes? Landes Bioscience 2012-10-15 3739 - 3744 Cell Cycle 11-20 Landes Bioscience DNA interstrand cross-links (ICLs) present a major challenge to cells, preventing separation of the two strands of duplex DNA and blocking major chromosome transactions, including transcription and replication. Due to the complexity of removing this form of DNA damage, no single DNA repair pathway has been shown to be capable of eradicating ICLs. In eukaryotes, ICL repair is a complex process, principally because several repair pathways compete for ICL repair intermediates in a strictly cell cycle-dependent manner. Yeast cells require a combination of nucleotide excision repair, homologous recombination repair and postreplication repair/translesion DNA synthesis to remove ICLs. There are also a number of additional ICL repair factors originally identified in the budding yeast Saccharomyces cerevisiae, called Pso1 though 10, of which Pso2 has an apparently dedicated role in ICL repair. Mammalian cells respond to ICLs by a complex network guided by factors mutated in the inherited cancer-prone disorder Fanconi anemia (FA). Although enormous progress has been made over recent years in identifying and characterizing FA factors as well as in elucidating certain aspects of the biology of FA, the mechanistic details of the ICL repair defects in FA patients remain unknown. Dissection of the FA DNA damage response pathway has, in part, been limited by the absence of FA-like pathways in highly tractable model organisms, such as yeast. Although S. cerevisiae possesses putative homologs of the FA factors FANCM, FANCJ and FANCP (Mph1, Chl1 and Slx4, respectively) as well as of the FANCM-associated proteins MHF1 and MHF2 (Mhf1 and Mhf2), the corresponding mutants display no significant increase in sensitivity to ICLs. Nevertheless, we and others have recently shown that these FA homologs, along with several other factors, control an ICL repair pathway, which has an overlapping or redundant role with a Pso2-controlled pathway. This pathway acts in S-phase and serves to prevent ICL-stalled replication forks from collapsing into DNA double-strand breaks. http://dx.doi.org/10.4161/cc.21727 http://www.landesbioscience.com/journals/cc/article/21727/ article Extra Views 1538-4101 Brad J. Niles and Ted Powers cc Plasma membrane proteins Slm1 and Slm2 mediate activation of the AGC kinase Ypk1 by TORC2 and sphingolipids in S. cerevisiae Landes Bioscience 2012-10-15 3745 - 3749 Cell Cycle 11-20 Landes Bioscience The PH domain-containing proteins Slm1 and Slm2 were originally identified as substrates of the rapamycin-insensitive TOR complex 2 (TORC2) and as mediators of signaling by the lipid second messenger phosphatidyl-inositol-4,5-bisphosphate (PI4,5P2) in budding yeast S. cerevisiae. More recently, these proteins have been identified as critical effectors that facilitate phosphorylation and activation of the AGC kinases Ypk1 and Ypk2 by TORC2.1 Here, we review the molecular basis for this regulation as well as place it within the context of recent findings that have revealed Slm1/2 and TORC2-dependent phosphorylation of Ypk1 is coupled to the biosynthesis of complex sphingolipids and to their levels within the plasma membrane (PM) as well as other forms of PM stress. Together, these studies reveal the existence of an intricate homeostatic feedback mechanism, whereby the activity of these signaling components is linked to the biosynthesis of PM lipids according to cellular need. http://dx.doi.org/10.4161/cc.21752 http://www.landesbioscience.com/journals/cc/article/21752/ article Extra Views 1538-4101 Liedewij Laan Sophie Roth and Marileen Dogterom cc End-on microtubule-dynein interactions and pulling-based positioning of microtubule organizing centers Landes Bioscience 2012-10-15 3750 - 3757 Cell Cycle 11-20 Landes Bioscience During important cellular processes such as centrosome and spindle positioning, dynein at the cortex interacts with dynamic microtubules in an apparent “end-on” fashion. It is well-established that dynein can generate forces by moving laterally along the microtubule lattice, but much less is known about dynein’s interaction with dynamic microtubule ends. In this paper, we review recent in vitro experiments that show that dynein, attached to an artificial cortex, is able to capture microtubule ends, regulate microtubule dynamics and mediate the generation of pulling forces on shrinking microtubules. We further review existing ideas on the involvement of dynein-mediated cortical pulling forces in the positioning of microtubule organizing centers such as centrosomes. Recent in vitro experiments have demonstrated that cortical pulling forces in combination with pushing forces can lead to reliable centering of microtubule asters in quasi two-dimensional microfabricated chambers. In these experiments, pushing leads to slipping of microtubule ends along the chamber boundaries, resulting in an anisotropic distribution of cortical microtubule contacts that favors centering, once pulling force generators become engaged. This effect is predicted to be strongly geometry-dependent, and we therefore finally discuss ongoing efforts to repeat these experiments in three-dimensional, spherical and deformable geometries. http://dx.doi.org/10.4161/cc.21753 http://www.landesbioscience.com/journals/cc/article/21753/ article Extra Views 1538-4101 Hongbo Ling Lirong Peng Edward Seto and Kenji Fukasawa cc Suppression of centrosome duplication and amplification by deacetylases Landes Bioscience 2012-10-15 3779 - 3791 Cell Cycle 11-20 Landes Bioscience Centrosome duplication is controlled both negatively and positively by a number of proteins. The activities and stabilities of those regulatory proteins are in many cases controlled by posttranslational modifications. Although acetylation and deacetylation are highly common posttranslational modifications, their roles in the regulation of centrosome duplication had not been closely examined. Here, through focusing on the deacetylases, we investigated the role of acetylation/deacetylation in the regulation of centrosome duplication and induction of abnormal amplification of centrosomes. We found that the deacetylation event negatively controls centrosome duplication and amplification. Of the 18 total known deacetylases (HDAC1–11, SIRT1–7), ten deacetylases possess the activity to suppress centrosome amplification, and their centrosome amplification suppressing activities are strongly associated with their abilities to localize to centrosomes. Among them, HDAC1, HDAC5 and SIRT1 show the highest suppressing activities, but each of them suppresses centrosome duplication and/or amplification with its unique mechanism. http://dx.doi.org/10.4161/cc.21985 http://www.landesbioscience.com/journals/cc/article/21985/ article Report 1538-4101 Pauline C. Conroy Chiara Saladino Tiago J. Dantas Pierce Lalor Peter Dockery and Ciaran G. Morrison cc C-NAP1 and rootletin restrain DNA damage-induced centriole splitting and facilitate ciliogenesis Landes Bioscience 2012-10-15 3769 - 3778 Cell Cycle 11-20 Landes Bioscience Cilia are found on most human cells and exist as motile cilia or non-motile primary cilia. Primary cilia play sensory roles in transducing various extracellular signals, and defective ciliary functions are involved in a wide range of human diseases. Centrosomes are the principal microtubule-organizing centers of animal cells and contain two centrioles. We observed that DNA damage causes centriole splitting in non-transformed human cells, with isolated centrioles carrying the mother centriole markers CEP170 and ninein but not kizuna or cenexin. Loss of centriole cohesion through siRNA depletion of C-NAP1 or rootletin increased radiation-induced centriole splitting, with C-NAP1-depleted isolated centrioles losing mother markers. As the mother centriole forms the basal body in primary cilia, we tested whether centriole splitting affected ciliogenesis. While irradiated cells formed apparently normal primary cilia, most cilia arose from centriolar clusters, not from isolated centrioles. Furthermore, C-NAP1 or rootletin knockdown reduced primary cilium formation. Therefore, the centriole cohesion apparatus at the proximal end of centrioles may provide a target that can affect primary cilium formation as part of the DNA damage response. http://dx.doi.org/10.4161/cc.21986 http://www.landesbioscience.com/journals/cc/article/21986/ article Report 1538-4101 Guoliang Wang Xiangyan Tong Stephanie Weng and Huilin Zhou cc Multiple phosphorylation of Rad9 by CDK is required for DNA damage checkpoint activation Landes Bioscience 2012-10-15 3792 - 3800 Cell Cycle 11-20 Landes Bioscience The DNA damage checkpoint controls cell cycle arrest in response to DNA damage, and activation of this checkpoint is in turn cell cycle-regulated. Rad9, the ortholog of mammalian 53BP1, is essential for this checkpoint response and is phosphorylated by the cyclin-dependent kinase (CDK) in the yeast Saccharomyces cerevisiae. Previous studies suggested that the CDK consensus sites of Rad9 are important for its checkpoint activity. However, the precise CDK sites of Rad9 involved have not been determined. Here we show that CDK consensus sites of Rad9 function in parallel to its BRCT domain toward checkpoint activation, analogous to its fission yeast ortholog Crb2. Unlike Crb2, however, mutation of multiple rather than any individual CDK site of Rad9 is required to completely eliminate its checkpoint activity in vivo. Although Dpb11 interacts with CDK-phosphorylated Rad9, we provide evidence showing that elimination of this interaction does not affect DNA damage checkpoint activation in vivo, suggesting that additional pathway(s) exist. Taken together, these findings suggest that the regulation of Rad9 by CDK and the role of Dpb11 in DNA damage checkpoint activation are more complex than previously suggested. We propose that multiple phosphorylation of Rad9 by CDK may provide a more robust system to allow Rad9 to control cell cycle-dependent DNA damage checkpoint activation. http://dx.doi.org/10.4161/cc.21987 http://www.landesbioscience.com/journals/cc/article/21987/ article Report 1538-4101 Paul Sirajuddin Sudeep Das Lymor Ringer Olga C. Rodriguez Angiela Sivakumar Yi-Chien Lee Aykut Üren Stanley T. Fricke Brian Rood Alpay Ozcan Sean S. Wang Sana Karam Venkata Yenugonda Patricia Salinas Emanuel Petricoin III Michael Pishvaian Michael P. Lisanti Yue Wang Richard Schlegel Bahram Moasser and Chris Albanese cc Quantifying the CDK inhibitor VMY-1-103’s activity and tissue levels in an in vivo tumor model by LC-MS/MS and by MRI Landes Bioscience 2012-10-15 3801 - 3809 Cell Cycle 11-20 Landes Bioscience The development of new small molecule-based therapeutic drugs requires accurate quantification of drug bioavailability, biological activity and treatment efficacy. Rapidly measuring these endpoints is often hampered by the lack of efficient assay platforms with high sensitivity and specificity. Using an in vivo model system, we report a simple and sensitive liquid chromatography-tandem mass spectrometry assay to quantify the bioavailability of a recently developed novel cyclin-dependent kinase inhibitor VMY-1-103, a purvalanol B-based analog whose biological activity is enhanced via dansylation. We developed a rapid organic phase extraction technique and validated wide and functional VMY-1-103 distribution in various mouse tissues, consistent with its enhanced potency previously observed in a variety of human cancer cell lines. More importantly, in vivo MRI and single voxel proton MR-Spectroscopy further established that VMY-1-103 inhibited disease progression and affected key metabolites in a mouse model of hedgehog-driven medulloblastoma. http://dx.doi.org/10.4161/cc.21988 http://www.landesbioscience.com/journals/cc/article/21988/ article Report 1538-4101 Yiping Huang Lauren N. Bell Jun Okamura Myoung Soo Kim Robert P. Mohney Rafael Guerrero-Preston and Edward A. Ratovitski cc Phospho-ΔNp63α/SREBF1 protein interactions: Bridging cell metabolism and cisplatin chemoresistance Landes Bioscience 2012-10-15 3810 - 3827 Cell Cycle 11-20 Landes Bioscience Tumor protein (TP)-p53 family members (TP63, TP63 and TP73) are guardians of the genome and key players in orchestrating the cellular response to cisplatin treatment. Cisplatin-induced phosphorylation of ΔNp63α was shown to have a role in regulating intracellular ΔNp63α protein levels. We previously found that squamous cell carcinoma (SCC) cells exposed to cisplatin displayed the ATM-dependent phosphorylation of ΔNp63α (p-ΔNp63α), which is critical for the transcriptional regulation of specific downstream mRNAs and microRNAs and is likely to underlie the chemoresistance of SCC cells. However, SCC cells expressing non-p-ΔNp63α became more cisplatin-resistant. We also found that p-ΔNp63α forms complexes with a number of proteins involved in cell death response through regulation of cell cycle arrest, apoptosis, autophagy, RNA splicing and chromatin modifications. Here, we showed that p-ΔNp63α induced ARG1, GAPDH, and CPT2 gene transcription in cisplatin-sensitive SCC cells, while non-p-ΔNp63α increased a transcription of CAD, G6PD and FASN genes in cisplatin-resistant SCC cells. We report that the p-ΔNp63α-dependent regulatory mechanisms implicated in the modulation of plethora of pathways, including amino acid, carbohydrate, lipid and nucleotide metabolisms, thereby affect tumor cell response to cisplatin-induced cell death, suggesting that the ATM-dependent ΔNp63α pathway plays a role in the resistance of tumor cells to platinum therapy. http://dx.doi.org/10.4161/cc.22022 http://www.landesbioscience.com/journals/cc/article/22022/ article Report 1538-4101 Irene Marchesi Francesco Paolo Fiorentino Flavio Rizzolio Antonio Giordano and Luigi Bagella cc The ablation of EZH2 uncovers its crucial role in rhabdomyosarcoma formation Landes Bioscience 2012-10-15 3828 - 3836 Cell Cycle 11-20 Landes Bioscience Rhabdomyosarcoma (RMS) is a pediatric tumor that arises from muscle precursor cells. RMS cells express several markers of early myogenic differentiation, but they fail to complete both differentiation program and cell cycle arrest, resulting in uncontrolled proliferation and incomplete myogenesis. Previous studies showed that EZH2, which is involved in both differentiation and cancer progression, is overexpressed in RMS, but a functional binding between its expression and its functional role in tumor formation or progression has not yet been demonstrated. We hypothesized that EZH2 is a key regulator of muscular differentiation program in RMS cells. In this study, we demonstrated that EZH2 directly binds muscle specific genes in RD cells. Silencing of EZH2 promotes the recruitment of a multiprotein complex at muscle-specific promoters, their transcriptional activation and protein expression. Moreover, we demonstrated that EZH2 is directly involved in transcriptional repression of MyoD, the main factor promoting myogenesis. EZH2 ablation induces MyoD activation the recovery of its binding on muscle-specific genes. http://dx.doi.org/10.4161/cc.22025 http://www.landesbioscience.com/journals/cc/article/22025/ article Report 1538-4101 Lenka Oplustilova Kamila Wolanin Martin Mistrik Gabriela Korinkova Dana Simkova Jan Bouchal Rene Lenobel Jirina Bartkova Alan Lau Mark J. O’Connor Jiri Lukas and Jiri Bartek cc Evaluation of candidate biomarkers to predict cancer cell sensitivity or resistance to PARP-1 inhibitor treatment Landes Bioscience 2012-10-15 3837 - 3850 Cell Cycle 11-20 Landes Bioscience Impaired DNA damage response pathways may create vulnerabilities of cancer cells that can be exploited therapeutically. One such selective vulnerability is the sensitivity of BRCA1- or BRCA2-defective tumors (hence defective in DNA repair by homologous recombination, HR) to inhibitors of the poly(ADP-ribose) polymerase-1 (PARP-1), an enzyme critical for repair pathways alternative to HR. While promising, treatment with PARP-1 inhibitors (PARP-1i) faces some hurdles, including (1) acquired resistance, (2) search for other sensitizing, non-BRCA1/2 cancer defects and (3) lack of biomarkers to predict response to PARP-1i. Here we addressed these issues using PARP-1i on 20 human cell lines from carcinomas of the breast, prostate, colon, pancreas and ovary. Aberrations of the Mre11-Rad50-Nbs1 (MRN) complex sensitized cancer cells to PARP-1i, while p53 status was less predictive, even in response to PARP-1i combinations with camptothecin or ionizing radiation. Furthermore, monitoring PARsylation and Rad51 foci formation as surrogate markers for PARP activity and HR, respectively, supported their candidacy for biomarkers of PARP-1i responses. As to resistance mechanisms, we confirmed the role of the multidrug resistance efflux transporters and its reversibility. More importantly, we demonstrated that shRNA lentivirus-mediated depletion of 53BP1 in human BRCA1-mutant breast cancer cells increased their resistance to PARP-1i. Given the preferential loss of 53BP1 in BRCA-defective and triple-negative breast carcinomas, our findings warrant assessment of 53BP1 among candidate predictive biomarkers of response to PARPi. Overall, this study helps characterize genetic and functional determinants of cellular responses to PARP-1i and contributes to the search for biomarkers to exploit PARP inhibitors in cancer therapy. http://dx.doi.org/10.4161/cc.22026 http://www.landesbioscience.com/journals/cc/article/22026/ article Report 1538-4101 Federico Pietrocola Guillermo Mariño Delphine Lissa Erika Vacchelli Shoaib Ahmad Malik Mireia Niso-Santano Naoufal Zamzami Lorenzo Galluzzi Maria Chiara Maiuri and Guido Kroemer cc Pro-autophagic polyphenols reduce the acetylation of cytoplasmic proteins Landes Bioscience 2012-10-15 3851 - 3860 Cell Cycle 11-20 Landes Bioscience Resveratrol is a polyphenol contained in red wine that has been amply investigated for its beneficial effects on organismal metabolism, in particular in the context of the so-called “French paradox,” i.e., the relatively low incidence of coronary heart disease exhibited by a population with a high dietary intake of cholesterol and saturated fats. At least part of the beneficial effect of resveratrol on human health stems from its capacity to promote autophagy by activating the NAD-dependent deacetylase sirtuin 1. However, the concentration of resveratrol found in red wine is excessively low to account alone for the French paradox. Here, we investigated the possibility that other mono- and polyphenols contained in red wine might induce autophagy while affecting the acetylation levels of cellular proteins. Phenolic compounds found in red wine, including anthocyanins (oenin), stilbenoids (piceatannol), monophenols (caffeic acid, gallic acid) glucosides (delphinidin, kuronamin, peonidin) and flavonoids (catechin, epicatechin, quercetin, myricetin), were all capable of stimulating autophagy, although with dissimilar potencies. Importantly, a robust negative correlation could be established between autophagy induction and the acetylation levels of cytoplasmic proteins, as determined by a novel immunofluorescence staining protocol that allows for the exclusion of nuclear components from the analysis. Inhibition of sirtuin 1 by both pharmacological and genetic means abolished protein deacetylation and autophagy as stimulated by resveratrol, but not by piceatannol, indicating that these compounds act through distinct molecular pathways. In support of this notion, resveratrol and piceatannol synergized in inducing autophagy as well as in promoting cytoplasmic protein deacetylation. Our results highlight a cause-effect relationship between the deacetylation of cytoplasmic proteins and autophagy induction by red wine components. http://dx.doi.org/10.4161/cc.22027 http://www.landesbioscience.com/journals/cc/article/22027/ article Report 1538-4101 Kamil Wolyniec Ai-Leen Chan Sue Haupt and Ygal Haupt cc Restoring PML tumor suppression to combat cancer Landes Bioscience 2012-10-15 3705 - 3706 Cell Cycle 11-20 Landes Bioscience http://dx.doi.org/10.4161/cc.22043 http://www.landesbioscience.com/journals/cc/article/22043/ article Editorials: Cell Cycle Features 1538-4101 Terunao Takahara and Tatsuya Maeda cc Stress granules: The last refuge of TORC1? Landes Bioscience 2012-10-15 3707 - 3708 Cell Cycle 11-20 Landes Bioscience http://dx.doi.org/10.4161/cc.22044 http://www.landesbioscience.com/journals/cc/article/22044/ article Editorials: Cell Cycle Features 1538-4101 Gergely Imre and Krishnaraj Rajalingam cc Role for caspase-2 during pore-forming toxin-mediated apoptosis Landes Bioscience 2012-10-15 3709 - 3710 Cell Cycle 11-20 Landes Bioscience http://dx.doi.org/10.4161/cc.22046 http://www.landesbioscience.com/journals/cc/article/22046/ article Editorials: Cell Cycle Features 1538-4101 Chih-Chien Tsai and Shih-Chieh Hung cc Functional roles of pluripotency transcription factors in mesenchymal stem cells Landes Bioscience 2012-10-15 3711 - 3712 Cell Cycle 11-20 Landes Bioscience http://dx.doi.org/10.4161/cc.22048 http://www.landesbioscience.com/journals/cc/article/22048/ article Editorials: Cell Cycle Features 1538-4101 Dapeng Zhang and L. Aravind cc Novel transglutaminase-like peptidase and C2 domains elucidate the structure, biogenesis and evolution of the ciliary compartment Landes Bioscience 2012-10-15 3861 - 3875 Cell Cycle 11-20 Landes Bioscience In addition to their role in motility, eukaryotic cilia serve as a distinct compartment for signal transduction and regulatory sequestration of biomolecules. Recent genetic and biochemical studies have revealed an extraordinary diversity of protein complexes involved in the biogenesis of cilia during each cell cycle. Mutations in components of these complexes are at the heart of human ciliopathies such as Nephronophthisis (NPHP), Meckel-Gruber syndrome (MKS), Bardet-Biedl syndrome (BBS) and Joubert syndrome (JBTS). Despite intense studies, proteins in some of these complexes, such as the NPHP1-4-8 and the MKS, remain poorly understood. Using a combination of computational analyses we studied these complexes to identify novel domains in them which might throw new light on their functions and evolutionary origins. First, we identified both catalytically active and inactive versions of transglutaminase-like (TGL) peptidase domains in key ciliary/centrosomal proteins CC2D2A/MKS6, CC2D2B, CEP76 and CCDC135. These ciliary TGL domains appear to have originated from prokaryotic TGL domains that act as peptidases, either in a prokaryotic protein degradation system with the MoxR AAA+ ATPase, the precursor of eukaryotic dyneins and midasins, or in a peptide-ligase system with an ATP-grasp enzyme comparable to tubulin-modifying TTL proteins. We suggest that active ciliary TGL proteins are part of a cilia-specific peptidase system that might remove tubulin modifications or cleave cilia- localized proteins, while the inactive versions are likely to bind peptides and mediate key interactions during ciliogenesis. Second, we observe a vast radiation of C2 domains, which are key membrane-localization modules, in multiple ciliary proteins, including those from the NPHP1-4-8 and the MKS complexes, such as CC2D2A/MKS6, RPGRIP1, RPGRIP1L, NPHP1, NPHP4, C2CD3, AHI1/Jouberin and CEP76, most of which can be traced back to the last eukaryotic ancestor. Identification of these TGL and C2 domains aid in the proper reconstruction of the Y-shaped linkers, which are key structures in the transitional zone of cilia, by allowing precise prediction of the multiple membrane-contacting and protein-protein interaction sites in these structures. These findings help decipher key events in the evolutionary separation of the ciliary and nuclear compartments in course of the emergence of the eukaryotic cell. http://dx.doi.org/10.4161/cc.22068 http://www.landesbioscience.com/journals/cc/article/22068/ article Report 1538-4101 Rhoda Stefanatos Ashwin Sriram Essi Kiviranta Aravind Mohan Victoria Ayala Howard T. Jacobs Reinald Pamplona and Alberto Sanz cc dj-1β regulates oxidative stress, insulin-like signaling and development in <italic>Drosophila melanogaster</italic> Landes Bioscience 2012-10-15 3876 - 3886 Cell Cycle 11-20 Landes Bioscience DJ-1 (or PARK-7) is a multifunctional protein implicated in numerous pathologies including cancer, sterility and Parkinson disease (PD). The popular genetic model Drosophila melanogaster has two orthologs, dj-1: α and β. Dysfunction of dj-1β strongly impairs fly mobility in an age-dependent manner. In this study, we analyze in detail the molecular mechanism underlying the dj-1β mutant phenotype. Mitochondrial hydrogen peroxide production, but not superoxide production, was increased in mutant flies. An increase in peroxide leak from mitochondria causes oxidative damage elsewhere and explains the strong reduction in mobility caused by dj-1β mutation. However, at the same time, increased levels of hydrogen peroxide activated a pro-survival program characterized by (1) an alteration in insulin-like signaling, (2) an increase in mitochondrial biogenesis and (3) an increase in the de-acetylase activity of sirtuins. The activation of this pro-survival program was associated with increased longevity under conditions of moderate oxidative stress. Additionally, the dj-1β mutation unexpectedly accelerated development, a phenotype not previously associated with this mutation. Our results reveal an important role of dj-1β in oxidative stress handling, insulin-like signaling and development in Drosophila melanogaster. http://dx.doi.org/10.4161/cc.22073 http://www.landesbioscience.com/journals/cc/article/22073/ article Report 1538-4101 Andrew Routh Tatiana Domitrovic and John E. Johnson cc Packaging host RNAs in small RNA viruses: An inevitable consequence of an error-prone polymerase? Landes Bioscience 2012-10-15 3713 - 3714 Cell Cycle 11-20 Landes Bioscience http://dx.doi.org/10.4161/cc.22112 http://www.landesbioscience.com/journals/cc/article/22112/ article Editorials: Cell Cycle Features 1538-4101 Cheng-Ming Chiang cc p53-Aurora A mitotic feedback loop regulates cell cycle progression and genomic stability Landes Bioscience 2012-10-15 3719 - 3719 Cell Cycle 11-20 Landes Bioscience http://dx.doi.org/10.4161/cc.22113 http://www.landesbioscience.com/journals/cc/article/22113/ article Cell Cycle News & Views 1538-4101 Theocharis Panaretakis cc Cisplatin-induced apoptosis and development of resistance are transcriptionally distinct processes Landes Bioscience 2012-10-15 3723 - 3723 Cell Cycle 11-20 Landes Bioscience http://dx.doi.org/10.4161/cc.22114 http://www.landesbioscience.com/journals/cc/article/22114/ article Cell Cycle News & Views 1538-4101 Roman V. Kondratov cc Cell-autonomous circadian DNA damage response: Is the case closed? Landes Bioscience 2012-10-15 3720 - 3720 Cell Cycle 11-20 Landes Bioscience http://dx.doi.org/10.4161/cc.22115 http://www.landesbioscience.com/journals/cc/article/22115/ article Cell Cycle News & Views 1538-4101 Zhi Yao and György Szabadkai cc Transcriptional profiling of apoptosis: Cell death classification moves toward the systems era Landes Bioscience 2012-10-15 3721 - 3721 Cell Cycle 11-20 Landes Bioscience http://dx.doi.org/10.4161/cc.22116 http://www.landesbioscience.com/journals/cc/article/22116/ article Cell Cycle News & Views 1538-4101 Vinata B. Lokeshwar cc Wee1-Hsp90 inhibitor combination treatment: Molecular therapy with potentially broad applicability Landes Bioscience 2012-10-15 3722 - 3722 Cell Cycle 11-20 Landes Bioscience http://dx.doi.org/10.4161/cc.22119 http://www.landesbioscience.com/journals/cc/article/22119/ article Cell Cycle News & Views 1538-4101 Irene López-Mateo M. Ángeles Villaronga Susana Llanos and Borja Belandia cc The transcription factor CREBZF is a novel positive regulator of p53 Landes Bioscience 2012-10-15 3887 - 3895 Cell Cycle 11-20 Landes Bioscience CREBZF is a member of the mammalian ATF/CREB family of transcription factors. Here, we describe a novel functional interaction between CREBZF and the tumor suppressor p53. CREBZF was identified in a yeast two-hybrid screen using HEY1, recently characterized as an indirect p53 activator, as bait. CREBZF interacts in vitro with both HEY1 and p53, and CREBZF expression stabilizes and activates p53. Moreover, CREBZF cooperates synergistically with HEY1 to enhance p53 transcriptional activity. On the other hand, partial depletion of endogenous CREBZF diminishes p53 protein levels and inhibits HEY1-mediated activation of p53. CREBZF-positive effects on p53 signaling may reflect, at least in part, an observed induction of posttranslational modifications in p53 known to prevent its degradation. CREBZF expression protects HCT116 cells from UV radiation-induced cell death. In addition, CREBZF expression confers sensitivity to 5-fluorouracil, a p53-activating chemotherapeutic drug. Our study suggests that CREBZF may participate in the modulation of p53 tumor suppressor function. http://dx.doi.org/10.4161/cc.22133 http://www.landesbioscience.com/journals/cc/article/22133/ article Report 1538-4101 Ravi K. Amaravadi cc Autophagy and tumor cell invasion Landes Bioscience 2012-10-15 3718 - 3718 Cell Cycle 11-20 Landes Bioscience http://dx.doi.org/10.4161/cc.22147 http://www.landesbioscience.com/journals/cc/article/22147/ article Cell Cycle News & Views 1538-4101 Carolina Vicente-Dueñas Isabel Romero-Camarero Francisco Javier García-Criado César Cobaleda and Isidro Sánchez-García cc The cellular architecture of multiple myeloma Landes Bioscience 2012-10-15 3715 - 3717 Cell Cycle 11-20 Landes Bioscience http://dx.doi.org/10.4161/cc.22178 http://www.landesbioscience.com/journals/cc/article/22178/ article Editorials: Cell Cycle Features 1538-4101 Carolina Vicente-Dueñas Inés González-Herrero María Begoña García Cenador Francisco Javier García Criado and Isidro Sánchez-García cc Loss of p53 exacerbates multiple myeloma phenotype by facilitating the reprogramming of hematopoietic stem/progenitor cells to malignant plasma cells by <italic>MafB</italic> Landes Bioscience 2012-10-15 3896 - 3900 Cell Cycle 11-20 Landes Bioscience Multiple myeloma (MM) is a serious, mostly incurable human cancer of malignant plasma cells. Chromosomal translocations affecting MAFB are present in a significant percentage of multiple myeloma patients. Genetically engineered Sca1-MafB mice, in which MafB expression is limited to hematopoietic stem/progenitor cells (HS/P-Cs), display the phenotypic features of MM. Contrary to many other types of cancer, it is not yet known if the p53 gene plays any essential role in the pathogenesis of this disease. Here, we show, taking advantage of the Sca1-MafB MM mouse model, that loss of p53 does not rescue the multiple myeloma disease, but instead accelerates its development and exacerbates the MM phenotype. Therefore, the efficiency of the MafB-induced MM reprogramming of normal HS/P-Cs to terminally differentiated malignant plasma cells is enhanced by p53 deficiency, in analogy to what happens in reprogramming to pluripotency. These results raise caution about interfering with p53 function when treating multiple myeloma. http://dx.doi.org/10.4161/cc.22186 http://www.landesbioscience.com/journals/cc/article/22186/ article Report 1538-4101 Isabelle Martins Antoine Tesniere Oliver Kepp Mickaël Michaud Frederic Schlemmer Laura Senovilla Claire Séror Didier Métivier Jean-Luc Perfettinic Laurence Zitvogel and Guido Kroemer cc Erratum to Martins I, et al. Cell Cycle Volume 8, Issue 22; pp. 3723–8 Landes Bioscience 2012-10-15 3901 - 3901 Cell Cycle 11-20 Landes Bioscience http://dx.doi.org/10.4161/cc.22442 http://www.landesbioscience.com/journals/cc/article/22442/ article Erratum