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1.
Integrating Rio1 activities discloses its nutrient-activated network in Saccharomyces cerevisiae.
Iacovella, MG, Bremang, M, Basha, O, Giacò, L, Carotenuto, W, Golfieri, C, Szakal, B, Dal Maschio, M, Infantino, V, Beznoussenko, GV, et al
Nucleic acids research. 2018;(15):7586-7611
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Abstract
The Saccharomyces cerevisiae kinase/adenosine triphosphatase Rio1 regulates rDNA transcription and segregation, pre-rRNA processing and small ribosomal subunit maturation. Other roles are unknown. When overexpressed, human ortholog RIOK1 drives tumor growth and metastasis. Likewise, RIOK1 promotes 40S ribosomal subunit biogenesis and has not been characterized globally. We show that Rio1 manages directly and via a series of regulators, an essential signaling network at the protein, chromatin and RNA levels. Rio1 orchestrates growth and division depending on resource availability, in parallel to the nutrient-activated Tor1 kinase. To define the Rio1 network, we identified its physical interactors, profiled its target genes/transcripts, mapped its chromatin-binding sites and integrated our data with yeast's protein-protein and protein-DNA interaction catalogs using network computation. We experimentally confirmed network components and localized Rio1 also to mitochondria and vacuoles. Via its network, Rio1 commands protein synthesis (ribosomal gene expression, assembly and activity) and turnover (26S proteasome expression), and impinges on metabolic, energy-production and cell-cycle programs. We find that Rio1 activity is conserved to humans and propose that pathological RIOK1 may fuel promiscuous transcription, ribosome production, chromosomal instability, unrestrained metabolism and proliferation; established contributors to cancer. Our study will advance the understanding of numerous processes, here revealed to depend on Rio1 activity.
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2.
Greatwall kinase at a glance.
Castro, A, Lorca, T
Journal of cell science. 2018;(20)
Abstract
Mitosis is controlled by a subtle balance between kinase and phosphatase activities that involve the master mitotic kinase cyclin-B-Cdk1 and its antagonizing protein phosphatase 2A-B55 (PP2A-B55). Importantly, the Greatwall (Gwl; known as Mastl in mammals, Rim15 in budding yeast and Ppk18 in fission yeast) kinase pathway regulates PP2A-B55 activity by phosphorylating two proteins, cAMP-regulated phosphoprotein 19 (Arpp19) and α-endosulfine (ENSA). This phosphorylation turns these proteins into potent inhibitors of PP2A-B55, thereby promoting a correct timing and progression of mitosis. In this Cell Science at a Glance article and the accompanying poster, we discuss how Gwl is regulated in space and time, and how the Gwl-Arpp19-ENSA-PP2A-B55 pathway plays an essential role in the control of M and S phases from yeast to human. We also summarize how Gwl modulates oncogenic properties of cells and how nutrient deprivation influences Gwl activity.
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Role of TGFBR1 and TGFBR2 genetic variants in Marfan syndrome.
De Cario, R, Sticchi, E, Lucarini, L, Attanasio, M, Nistri, S, Marcucci, R, Pepe, G, Giusti, B
Journal of vascular surgery. 2018;(1):225-233.e5
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Abstract
OBJECTIVE Genetic variants in transforming growth factor beta (TGF-β) receptors type 1 (TGFBR1) and type 2 (TGFBR2) genes have been associated with different hereditary connective tissue disorders sharing thoracic aortic aneurysm and dissection (TAA/D). Mutations in both TGFBR1/2 genes have been described in patients with TAA/D and Marfan syndrome (MFS), and they are associated consistently with Loeys-Dietz syndrome. The existing literature shows discordant data resulting from mutational screening of TGFBR1/2 genes in patients with MFS. The aim of the study was to investigate the role of TGFBR1/2 genetic variants in determining and/or modulating MFS clinical phenotype. METHODS We investigated 75 unrelated patients with MFS referred to the Center for Marfan Syndrome and Related Disorders (Careggi University Hospital, Florence) who were subjected to FBN1 and TGFBR1/2 Sanger mutational screening. RESULTS Forty-seven patients with MFS (63%) carried a pathogenetic FBN1 mutation. No pathogenetic mutations were detected in TGFBR1/2 genes. Ten common polymorphisms were identified in TGFBR2 and 6 in TGFBR1. Their association with cardiovascular manifestations was evaluated. Carriers of the A allele of rs11466512, delA allele of c.383delA or delT allele of c.1256-15del1T polymorphisms had a trend toward or significantly reduced z-scores (median [interquartile range (IQR)], 2.2 [1.13-4.77]; 2.1 [1.72-3.48]; 2.5 [1.85-3.86]) with respect to homozygous patients with wild-type MFS (median [IQR], 4.20 [2.39-7.25]; 3.9 [2.19-7.00]; 3.9 [2.14-6.93]). Carriers of the A allele of the rs2276767 polymorphism showed a trend toward increased z-score (median [IQR], 4.9 [2.14-7.16]) with respect to patients with wild-type MFS (median [IQR], 3.3 [1.75-5.45]). The protective effect of TGFBR1/2 genetic score including all the 4 variants was also evaluated. Patients with MFS with two or more protective alleles included in the score had statistically significant reduced aortic z-scores (median [IQR], 2.20 [1.48-3.37]) with respect to patients with 1 or no protective alleles (median [IQR], 4.20 [2.48-7.12]; P = .007). Patients with severe aortic manifestations (aortic z-score ≥ 2 or aortic surgery) showed a significantly lower prevalence of subjects with two or more protective alleles included in the genetic score (29.7%) than patients with no or milder cardiovascular involvement (63.6%; P = .029). The genetic score protective effect on global aortic manifestations severity (aortic z-score ≥ 2 or aortic surgery) was also observed at the logistic regression analysis adjusted for the presence of FBN1 gene mutations (odds ratio, 0.21; 95% CI, 0.05-0.84; P = .028). CONCLUSIONS In conclusion, our data reappraise the role of TGFBR1 and TGFBR2 as major genes in patients with MFS, and suggest that TGFBR1/2 genetic variants (in particular when evaluated as a burden by score) might play a role in modulating the severity of cardiovascular manifestation in MFS.
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Impact of genetic variations in the MAPK signaling pathway on outcome in metastatic colorectal cancer patients treated with first-line FOLFIRI and bevacizumab: data from FIRE-3 and TRIBE trials.
Berger, MD, Stintzing, S, Heinemann, V, Yang, D, Cao, S, Sunakawa, Y, Ning, Y, Matsusaka, S, Okazaki, S, Miyamoto, Y, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2017;(11):2780-2785
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Abstract
BACKGROUND The MAPK-interacting kinase 1 (MKNK1) is localized downstream of the RAS/RAF/ERK and the MAP3K1/MKK/p38 signaling pathway. Through phosphorylation MKNK1 regulates the function of eukaryotic translation initiation factor 4E, a key player in translational control, whose expression is often upregulated in metastatic colorectal cancer patients (mCRC). Preclinical data suggest that MKNK1 increases angiogenesis by upregulating angiogenic factors. We therefore hypothesize that variations in the MKNK1 gene predict outcome in mCRC patients treated with first-line FOLFIRI and bevacizumab (bev). PATIENTS AND METHODS A total of 567 patients with KRAS wild-type mCRC in the randomized phase III FIRE-3 and TRIBE trials treated with first-line FOLFIRI/bev (discovery and validation cohorts) or FOLFIRI and cetuximab (cet) (control cohort) were included in this study. Five single-nucleotide polymorphisms in the MAPK signaling pathway were analyzed. RESULTS AA genotype carriers of the MKNK1 rs8602 single-nucleotide polymorphism treated with FOLFIRI/bev in the discovery cohort (FIRE-3) had a shorter progression-free survival (PFS) than those harboring any C (7.9 versus 10.3 months, Hazard ratio (HR) 1.73, P = 0.038). This association could be confirmed in the validation cohort (TRIBE) in multivariable analysis (PFS 9.0 versus 11.0 months, HR 3.04, P = 0.029). Furthermore, AA carriers in the validation cohort had a decreased overall response rate (25% versus 66%, P = 0.049). Conversely, AA genotype carriers in the control group receiving FOLFIRI/cet did not show a shorter PFS. By combining both FOLFIRI/bev cohorts the worse outcome among AA carriers became more significant (PFS 9.0 versus 10.5 months) in univariable (HR 1.74, P = 0.015) and multivariable analysis (HR 1.76, P = 0.022). Accordingly, AA carriers did also exhibit an inferior overall response rate compared with those harboring any C (36% versus 65%, P = 0.005). CONCLUSION MKNK1 polymorphism rs8602 might serve as a predictive marker in KRAS wild-type mCRC patients treated with FOLFIRI/bev in the first-line setting. Additionally, MKNK1 might be a promising target for drug development.
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Arthrogryposis as neonatal presentation of Loeys-Dietz syndrome due to a novel TGFBR2 mutation.
Valenzuela, I, Fernández-Alvarez, P, Munell, F, Sanchez-Montanez, A, Giralt, G, Vendrell, T, Tizzano, EF
European journal of medical genetics. 2017;(6):303-307
Abstract
Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized mainly by cardiovascular, craniofacial and skeletal features. We report on a patient with LDS, whose prenatal examination was compatible with the diagnosis of arthrogryposis multiplex congenita. Neonatal assessment showed craniofacial and cardiovascular findings suggestive of LDS whose diagnosis was confirmed by the detection of a novel mutation (HGVN: NM_003242.5 (TGFBR2): c.1381T > C (p.(Cys461Arg))) in the TGFBR2 gene. Few prenatal and neonatal cases of LDS have been reported in the literature. We reviewed all cases reported to date with perinatal onset to delineate the clinical manifestations that allow us to prompt diagnosis of this syndrome at an early stage to prevent fatal cardiovascular complications. Furthermore we discuss the multidisciplinary follow up required in these patients.
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DRD2: Bridging the Genome and Ingestive Behavior.
Sun, X, Luquet, S, Small, DM
Trends in cognitive sciences. 2017;(5):372-384
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Abstract
Recent work highlights the importance of genetic variants that influence brain structure and function in conferring risk for polygenic obesity. The neurotransmitter dopamine (DA) has a pivotal role in energy balance by integrating metabolic signals with circuits supporting cognitive, perceptual, and appetitive functions that guide feeding. It has also been established that diet and obesity alter DA signaling, leading to compulsive-like feeding and neurocognitive impairments. This raises the possibility that genetic variants that influence DA signaling and adaptation confer risk for overeating and cognitive decline. Here, we consider the role of two common gene variants, FTO and TaqIA rs1800497 in driving gene × environment interactions promoting obesity, metabolic dysfunction, and cognitive change via their influence on DA receptor subtype 2 (DRD2) signaling.
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Hippo Signaling in the Liver Regulates Organ Size, Cell Fate, and Carcinogenesis.
Patel, SH, Camargo, FD, Yimlamai, D
Gastroenterology. 2017;(3):533-545
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Abstract
The Hippo signaling pathway, also known as the Salvador-Warts-Hippo pathway, is a regulator of organ size. The pathway takes its name from the Drosophila protein kinase, Hippo (STK4/MST1 and STK3/MST2 in mammals), which, when inactivated, leads to considerable tissue overgrowth. In mammals, MST1 and MST2 negatively regulate the transcriptional co-activators yes-associated protein 1 and WW domain containing transcription regulator 1 (WWTR1/TAZ), which together regulate expression of genes that control proliferation, survival, and differentiation. Yes-associated protein 1 and TAZ activation have been associated with liver development, regeneration, and tumorigenesis. How their activity is dynamically regulated in these contexts is just beginning to be elucidated. We review the mechanisms of Hippo signaling in the liver and explore outstanding questions for future research.
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Designing and optimization of novel human LMTK3 inhibitors against breast cancer - a computational approach.
Anbarasu, K, Jayanthi, S
Journal of receptor and signal transduction research. 2017;(1):51-59
Abstract
Estrogen receptor-α (ERα) is expressed more in patients with breast cancer and its level correlated with endocrine resistance. LMTK3 is reported as breast cancer target with regulation of estrogen receptor-α (ERα) through phosphorylation. In this computational study, structure-based inhibitor screening was performed on human LMTK3 using ZINC database. ATP-binding cavity with critical residues involved in the LMTK3 phosphorylation was used as target site for the screening. From the large ligand library, the best compounds were screen with three-phase virtual screening methods in Dockblaster, AutoDock Vina and AutoDock, respectively. The evaluation of ligands was carried out by binding energy and weak interactions, such as hydrogen bond interactions and hydrophobic contacts, in the target site that favors LMTK3 inhibition. Top compounds were found to be more effective in druglikeness activity by ADME prediction. The stability and binding affinity of ligand complexes were optimized by trajectory analysis such as RMSD, Rg, SASA and interhydrogen bonds from molecular dynamics simulations. The behavior of protein motion after ligand binding was illustrated by eigenvectors from principal component analysis (PCA). In addition, binding free energy of the LMTK3-ligand complexes were calculated by MM/PBSA methods and results supported the strong binding in dynamic system. Thus, the computational studies illustrated the structural insights on LMTK3 inhibition mechanism by ligands ZINC04670539, ZINC05607079 and ZINC04344028, also proposed as potent lead candidates. Our findings step towards developing novel LMTK3 inhibitors and identified lead candidates can be future breast cancer drugs with further experimental studies.
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Association of Mutations in TBK1 With Sporadic and Familial Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.
Freischmidt, A, Müller, K, Ludolph, AC, Weishaupt, JH, Andersen, PM
JAMA neurology. 2017;(1):110-113
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative syndromes that occur sporadically or have been associated with mostly dominant inheritance of mutations in more than 30 genes. A critical issue is whether all reported mutations are disease causing or are coincidental findings. In this review we analyze the pathogenicity of nonsynonymous variants in the newly discovered gene encoding TANK-binding kinase 1 (TBK1). The available data suggest that mutations in TBK1 that cause a 50% reduction of TBK1 protein levels are pathogenic. In most cases, the almost complete loss of expression of the mutated TBK1 allele is due to loss-of-function mutations creating a premature termination codon and the degradation of the mutated messenger RNA by nonsense-mediated messenger RNA decay. In addition, TBK1 protein levels reduced by 50% have been proven for specific in-frame deletions of 1 or several amino acids, probably due to increased degradation of the mutated protein. Evaluation of many of the TBK1 missense mutations found in patients with ALS or FTD is prevented by missing data demonstrating cosegregation of the variants and incomplete knowledge about the TBK1 functions relevant for neurodegeneration. These findings suggest that haploinsufficiency of TBK1 is causative for ALS and FTD regardless of the type of mutation. Evaluation of TBK1 variants that do not cause haploinsufficiency is not possible without data demonstrating cosegregation.
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YAP/TAZ-mediated activation of serine metabolism and methylation regulation is critical for LKB1-deficient breast cancer progression.
Wu, Q, Li, J, Sun, S, Chen, X, Zhang, H, Li, B, Sun, S
Bioscience reports. 2017;(5)
Abstract
The crucial interplay between metabolic remodeling and the epigenetics could contribute to promote cancer progression. A remarkable association within interaction, LKB1 has been reported, suggesting that the expression of key enzymes involving de novo serine synthesis and DNA methyltransferases like DNMT1 and DNMT3A increase LKB1-deficiency cells. However, the complex interactional link between metabolic remodeling and the epigenetics is still unclear. Hence, we focus on the relationship between YAP/TAZ and serine metabolism to control methylation of DNA or histone in breast cancer with LKB1 deficiency. We hypothesize that YAP/TAZ may have the function to activate key enzymes involving serine metabolism like PSPH and up-regulate the amino acid transporters to supply sources of serine synthesis through activation of C-MYC with TEAD1. Further, we speculate that YAP/TAZ in dependent of FOS may promote DNMT1 and subsequently mediate DNMT1-G9A complex involving serine metabolism and the methylation of DNA and histone. We hope that our study will stimulate further studies and a new targeted therapy and early medical intervention for YAP/TAZ could be a useful option for breast cancer cases complicated with LKB1 deficiency.