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https://www.readbyqxmd.com/read/28102848/statins-in-anthracycline-induced-cardiotoxicity-rac-and-rho-and-the-heartbreakers
#1
REVIEW
Christian Henninger, Gerhard Fritz
Cancer patients receiving anthracycline-based chemotherapy are at risk to develop life-threatening chronic cardiotoxicity with the pathophysiological mechanism of action not fully understood. Besides the most common hypothesis that anthracycline-induced congestive heart failure (CHF) is mainly caused by generation of reactive oxygen species, recent data point to a critical role of topoisomerase II beta (TOP2B), which is a primary target of anthracycline poisoning, in the pathophysiology of CHF. As the use of the only clinically approved cardioprotectant dexrazoxane has been limited by the FDA in 2011, there is an urgent need for alternative cardioprotective measures...
January 19, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28102564/pkn2-is-essential-for-mouse-embryonic-development-and-proliferation-of-mouse-fibroblasts
#2
Sally Danno, Koji Kubouchi, Mona Mehruba, Manabu Abe, Rie Natsume, Kenji Sakimura, Satoshi Eguchi, Masahiro Oka, Masanori Hirashima, Hiroki Yasuda, Hideyuki Mukai
PKN2, a member of the protein kinase N (PKN) family, has been suggested by in vitro culture cell experiments to bind to Rho/Rac GTPases and contributes to cell-cell contact and cell migration. To unravel the in vivo physiological function of PKN2, we targeted the PKN2 gene. Constitutive disruption of the mouse PKN2 gene resulted in growth retardation and lethality before embryonic day (E) 10.5. PKN2(-/-) embryo did not undergo axial turning and showed insufficient closure of the neural tube. Mouse embryonic fibroblasts (MEFs) derived from PKN2(-/-) embryos at E9...
January 19, 2017: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://www.readbyqxmd.com/read/28102109/epigenetic-regulation-of-rgs2-regulator-of-g-protein-signaling-2-in-chemoresistant-ovarian-cancer-cells
#3
Ercan Cacan
Regulator of G-protein signaling 2 (RGS2) is a GTPase-activating protein functioning as an inhibitor of G-protein coupled receptors (GPCRs). RGS2 dysregulation was implicated in solid tumour development and RGS2 downregulation has been reported in prostate and ovarian cancer progression. However, the molecular mechanism by which RGS2 expression is suppressed in ovarian cancer remains unknown. The expression and epigenetic regulation of RGS2 in chemosensitive and chemoresistant ovarian cancer cells were determined by qRT-PCR and chromatin immunoprecipitation assays, respectively...
January 19, 2017: Journal of Chemotherapy
https://www.readbyqxmd.com/read/28101920/quantitative-proteomic-analysis-of-hiv-1-tat-induced-dysregulation-in-sh-sy5y-neuroblastoma-cells
#4
Tariq Ganief, Putuma Gqamana, Shaun Garnett, Jackie Hoare, Dan J Stein, John Joska, Nelson Soares, Jonathan M Blackburn
Despite affecting up to 70% of HIV-positivepatients and being the leading cause of dementia in patients under 40 years, the molecular mechanisms involved in the onset of HIV-associated neurocognitive disorders (HAND) are not well understood. To address this, we performed SILAC-based quantitative proteomic analysis on HIV-Tat treated SH-SY5Y neuroblastoma cells. Isolated protein was fractionated by SDS-PAGE and analysed by nLC-MS/MS on an Orbitrap Velos. Using MaxQuant, we identified and quantified 3077 unique protein groups, of which 407 were differentially regulated...
January 19, 2017: Proteomics
https://www.readbyqxmd.com/read/28100775/cool-associated-tyrosine-phosphorylated-protein-1-is-required-for-the-anchorage-independent-growth-of-cervical-carcinoma-cells-by-binding-paxillin-and-promoting-akt-activation
#5
Sungsoo M Yoo, Arash Latifkar, Richard A Cerione, Marc A Antonyak
Cool-associated tyrosine phosphorylated protein-1 (Cat-1) is a signaling scaffold, as well as an ADP-ribosylation factor-GTPase-activating protein (ARF-GAP). Although best known for its role in cell migration, we recently showed that the ability of Cat-1 to bind paxillin, a major constituent of focal complexes, was also essential for the anchorage-independent growth of HeLa cervical carcinoma cells. Here, we set out to learn more about the underlying mechanism by which Cat-paxillin interactions mediate this effect...
January 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28100513/loss-of-ranbp2-in-motor-neurons-causes-the-disruption-of-nucleocytoplasmic-and-chemokine-signaling-and-proteostasis-of-hnrnph3-and-mmp28-and-the-development-of-amyotrophic-lateral-sclerosis-als-like-syndromes
#6
Kyoung-In Cho, Dosuk Yoon, Sunny Qiu, Zachary Danziger, Warren M Grill, William C Wetsel, Paulo A Ferreira
The pathogenic drivers of sporadic and familial motor neuron disease (MND), such ALS, are unknown. MND impair the Ran GTPase cycle, which controls nucleocytoplasmic transport, ribostasis and proteostasis; however, cause-effect mechanisms of Ran GTPase modulators in motoneuron pathobiology are heretofore elusive. The cytosolic and peripheral nucleoporin, Ranbp2, is a critical regulator of the Ran GTPase cycle and proteostasis of neurological disease-prone substrates, but the roles of Ranbp2 in motoneuron biology and disease remain unknown...
January 18, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28099845/absence-of-neurofibromin-induces-an-oncogenic-metabolic-switch-via-mitochondrial-erk-mediated-phosphorylation-of-the-chaperone-trap1
#7
Ionica Masgras, Francesco Ciscato, Anna Maria Brunati, Elena Tibaldi, Stefano Indraccolo, Matteo Curtarello, Federica Chiara, Giuseppe Cannino, Elena Papaleo, Matteo Lambrughi, Giulia Guzzo, Alberto Gambalunga, Marco Pizzi, Vincenza Guzzardo, Massimo Rugge, Stefania Edith Vuljan, Fiorella Calabrese, Paolo Bernardi, Andrea Rasola
Mutations in neurofibromin, a Ras GTPase-activating protein, lead to the tumor predisposition syndrome neurofibromatosis type 1. Here, we report that cells lacking neurofibromin exhibit enhanced glycolysis and decreased respiration in a Ras/ERK-dependent way. In the mitochondrial matrix of neurofibromin-deficient cells, a fraction of active ERK1/2 associates with succinate dehydrogenase (SDH) and TRAP1, a chaperone that promotes the accumulation of the oncometabolite succinate by inhibiting SDH. ERK1/2 enhances both formation of this multimeric complex and SDH inhibition...
January 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/28098758/neurotrophin-promotes-neurite-outgrowth-by-inhibiting-rif-gtpase-activation-downstream-of-mapks-and-pi3k-signaling
#8
Xiaoxia Tian, Huijuan Yan, Jiayi Li, Shuang Wu, Junyu Wang, Lifei Fan
Members of the well-known semaphorin family of proteins can induce both repulsive and attractive signaling in neural network formation and their cytoskeletal effects are mediated in part by small guanosine 5'-triphosphatase (GTPases). The aim of this study was to investigate the cellular role of Rif GTPase in the neurotrophin-induced neurite outgrowth. By using PC12 cells which are known to cease dividing and begin to show neurite outgrowth responding to nerve growth factor (NGF), we found that semaphorin 6A was as effective as nerve growth factor at stimulating neurite outgrowth in PC12 cells, and that its neurotrophic effect was transmitted through signaling by mitogen-activated protein kinases (MAPKs) and phosphatidylinositol-3-kinase (PI3K)...
January 13, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28098754/drp1-dependent-mitochondrial-fission-plays-critical-roles-in-physiological-and-pathological-progresses-in-mammals
#9
REVIEW
Chenxia Hu, Yong Huang, Lanjuan Li
Current research has demonstrated that mitochondrial morphology, distribution, and function are maintained by the balanced regulation of mitochondrial fission and fusion, and perturbation of the homeostasis between these processes has been related to cell or organ dysfunction and abnormal mitochondrial redistribution. Abnormal mitochondrial fusion induces the fragmentation of mitochondria from a tubular morphology into pieces; in contrast, perturbed mitochondrial fission results in the fusion of adjacent mitochondria...
January 13, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28098342/the-evolution-of-rgs-proteins-as-drug-targets-20%C3%A2-years-in-the-making-iuphar-review-x
#10
REVIEW
B Sjögren
Regulators of G protein signaling (RGS) proteins are celebrating the 20(th) anniversary of their discovery. The unveiling of this new family of negative regulators of G protein signaling in the mid-1990's solved a persistent conundrum in the G protein signaling field, in which the rate of deactivation of signaling cascades in vivo could not be replicated in exogenous systems. Since then, there has been tremendous advancement in the knowledge of RGS protein structure, function, regulation and their role as novel drug targets...
January 18, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28098232/crystal-structure-of-sec10-a-subunit-of-the-exocyst-complex
#11
Jianxing Chen, Atsushi Yamagata, Keiko Kubota, Yusuke Sato, Sakurako Goto-Ito, Shuya Fukai
The exocyst complex is a heterooctameric protein complex composed of Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70 and Exo84. This complex plays an essential role in trafficking secretory vesicles to the plasma membrane through its interaction with phosphatidylinositol 4,5-bisphosphate and small GTPases. To date, the near-full-length structural information of each subunit has been limited to Exo70, although the C-terminal half structures of Sec6, Sec15 and Exo84 and the structures of the small GTPase-binding domains of Sec3, Sec5 and Exo84 have been reported...
January 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28096346/conserved-gtpase-lepa-elongation-factor-4-functions-in-biogenesis-of-the-30s-subunit-of-the-70s-ribosome
#12
Michelle R Gibbs, Kyung-Mee Moon, Menglin Chen, Rohan Balakrishnan, Leonard J Foster, Kurt Fredrick
The physiological role of LepA, a paralog of EF-G found in all bacteria, has been a mystery for decades. Here, we show that LepA functions in ribosome biogenesis. In cells lacking LepA, immature 30S particles accumulate. Four proteins are specifically underrepresented in these particles-S3, S10, S14, and S21-all of which bind late in the assembly process and contribute to the folding of the 3' domain of 16S rRNA. Processing of 16S rRNA is also delayed in the mutant strain, as indicated by increased levels of precursor 17S rRNA in assembly intermediates...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28096337/stress-granule-associated-protein-g3bp2-regulates-breast-tumor-initiation
#13
Nisha Gupta, Mark Badeaux, Yiqian Liu, Kamila Naxerova, Dennis Sgroi, Lance L Munn, Rakesh K Jain, Igor Garkavtsev
Breast tumors contain tumorigenic cancer cells, termed "tumor-initiating cells" (TICs), which are capable of both replenishing themselves and giving rise to populations of nontumorigenic breast cancer cells (non-TICs). However, the molecular mechanisms responsible for breast tumor initiation remain poorly understood. Here we describe a chemical screening strategy to identify small molecules that enhance the effect of chemotherapeutic agents on TIC-enriched breast cancer cells. We identified proteins that interact with the lead compound C108, including the stress granule-associated protein, GTPase-activating protein (SH3 domain)-binding protein 2, G3BP2...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28095620/tools-for-live-imaging-of-active-rho-gtpases-in-xenopus
#14
REVIEW
Rachel E Stephenson, Ann L Miller
Rho family GTPases are signaling molecules that orchestrate cytoskeletal dynamics in a variety of cellular processes. Because they effect localized changes to the cytoskeleton only in their active (GTP-bound) conformation, the ability to monitor the active state of Rho GTPases in space and time is critical for understanding their function. Here, we summarize popular tools used for live imaging of active Rho GTPases, outlining advantages and drawbacks of these approaches. Additionally, we highlight key features of the Xenopus laevis embryo that make it well-suited for epithelial cell biology and discuss how application of Rho activity reporters in the Xenopus laevis embryo led to the discovery of a novel phenomenon, junctional Rho flares...
January 17, 2017: Genesis: the Journal of Genetics and Development
https://www.readbyqxmd.com/read/28092672/bpgap1-spatially-integrates-jnk-erk-signaling-crosstalk-in-oncogenesis
#15
T Jiang, C Q Pan, B C Low
Simultaneous hyperactivation of stress-activated protein kinase/c-Jun N-terminal protein kinase (SAPK/JNK) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling cascades has been reported in carcinogenesis. However, how they are integrated to promote oncogenesis remains unknown. By analyzing breast invasive carcinoma database (The Cancer Genome Altas), we found that the mRNA expression levels of both JNK1 and ERK2 are positively correlated with the mRNA level of EEA1, an endosome associated protein, indicating the potential JNK/ERK crosstalk at endosome...
January 16, 2017: Oncogene
https://www.readbyqxmd.com/read/28092360/chemical-proteomics-reveals-adp-ribosylation-of-small-gtpases-during-oxidative-stress
#16
Nathan P Westcott, Joseph P Fernandez, Henrik Molina, Howard C Hang
ADP-ribosylation is a post-translational modification that is known to be involved in cellular homeostasis and stress but has been challenging to analyze biochemically. To facilitate the detection of ADP-ribosylated proteins, we show that an alkyne-adenosine analog, N(6)-propargyl adenosine (N(6)pA), is metabolically incorporated in mammalian cells and enables fluorescence detection and proteomic analysis of ADP-ribosylated proteins. Notably, our analysis of N(6)pA-labeled proteins that are upregulated by oxidative stress revealed differential ADP-ribosylation of small GTPases...
January 16, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28090783/probing-the-druggability-of-membrane-bound-rab5-by-molecular-dynamics-simulations
#17
Eileen Edler, Matthias Stein
Rab5 is a small GTPase and a key regulator in early endosomal trafficking. Rab5 and its effectors are involved in a large number of infectious diseases and certain types of cancer. We performed µs atomistic molecular dynamics simulations of inactive and active full-length Rab5 anchored to a complex model bilayer with composition of the early endosome membrane. Direct interactions between the Rab5 G domain and the bilayer were observed. We found two dominant nucleotide-dependent orientations characterised by a different accessibility of the switch regions...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
https://www.readbyqxmd.com/read/28090373/hgbp-1-expression-predicts-shorter-progression-free-survival-in-ovarian-cancers-while-contributing-to-paclitaxel-resistance
#18
Suzan Wadi, Aaron R Tipton, Jill A Trendel, Sadik A Khuder, Deborah J Vestal
Ovarian cancer is the gynecological cancer with the poorest prognosis. One significant reason is the development of resistance to the chemotherapeutic drugs used in its treatment. The large GTPase, hGBP-1, has been implicated in paclitaxel resistance in ovarian cell lines. Forced expression of hGBP-1 in SKOV3 ovarian cancer cells protects them from paclitaxel-induced cell death. However, prior to this study, nothing was known about whether hGBP-1 was expressed in ovarian tumors and whether its expression correlated with paclitaxel resistance...
December 2016: Journal of Cancer Therapy
https://www.readbyqxmd.com/read/28089989/rhoa-regulates-actin-network-dynamics-during-apical-surface-emergence-in-multiciliated-epithelial-cells
#19
Jakub Sedzinski, Edouard Hannezo, Fan Tu, Maté Biro, John B Wallingford
Homeostatic replacement of epithelial cells from basal precursors is a multistep process involving progenitor cell specification, radial intercalation and, finally, apical surface emergence. Recent data demonstrate that actin-based pushing under the control of the formin protein Fmn1 drives apical emergence in nascent multiciliated epithelial cells (MCCs), but little else is known about this actin network or the control of Fmn1. Here, we explore the role of the small GTPase RhoA in MCC apical emergence. Disruption of RhoA function reduced the rate of apical surface expansion and decreased the final size of the apical domain...
January 15, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28089905/nudix-type-motif-2-contributes-to-cancer-proliferation-through-the-regulation-of-rag-gtpase-mediated-mammalian-target-of-rapamycin-complex-1-localization
#20
Ohman Kwon, Dongoh Kwak, Sang Hoon Ha, Hyeona Jeon, Mangeun Park, Yeonho Chang, Pann-Ghill Suh, Sung Ho Ryu
Lysosomal localization of mammalian target of rapamycin complex 1 (mTORC1) is a critical step for activation of the molecule. Rag GTPases are essential for this translocation. Here, we demonstrate that Nudix-type motif 2 (NUDT2) is a novel positive regulator of mTORC1 activation. Activation of mTORC1 is impaired in NUDT2-silenced cells. Mechanistically, NUDT2 binds to Rag GTPase and controls mTORC1 translocation to the lysosomal membrane. Furthermore, NUDT2-dependent mTORC1 regulation is critical for proliferation of breast cancer cells, as NUDT2-silenced cells arrest in G0/G1 phases...
January 12, 2017: Cellular Signalling
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