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https://www.readbyqxmd.com/read/29644085/protein-molecular-modeling-shows-residue-t599-is-critical-to-wild-type-function-of-polg-and-description-of-a-novel-variant-associated-with-the-sando-phenotype
#1
John E Richter, Hector G Robles, Elizabeth Mauricio, Ahmed Mohammad, Paldeep S Atwal, Thomas R Caulfield
Sensory ataxic neuropathy with dysarthria and ophthalmoparesis (SANDO) is a rare phenotype resulting from pathogenic variants of mitochondrial DNA polymerase gamma ( POLG ). We modeled a novel POLG variant, T599P, that causes the SANDO phenotype and another variant at the same residue, p.T599E, to observe their effect on protein function and confirm the pathogenicity of T599P. Through neoteric molecular modeling techniques, we show that changes at the T599 residue position introduce extra rigidity into the surrounding helix-loop-helix, which places steric pressure on nearby nucleotides...
2018: Human Genome Variation
https://www.readbyqxmd.com/read/29581274/loss-of-tdp43-inhibits-progression-of-triple-negative-breast-cancer-in-coordination-with-srsf3
#2
Hao Ke, Limin Zhao, Honglei Zhang, Xu Feng, Haibo Xu, Junjun Hao, Shaowei Wang, Qin Yang, Li Zou, Xiaosan Su, Liqiong Wang, Chunlian Wu, Yang Wang, Jianyun Nie, Baowei Jiao
Aberrant alternative splicing has been highlighted as a potential hallmark of cancer. Here, we identify TDP43 (TAR DNA-binding protein 43) as an important splicing regulator responsible for the unique splicing profile in triple-negative breast cancer (TNBC). Clinical data demonstrate that TDP43 is highly expressed in TNBC with poor prognosis. Knockdown of TDP43 inhibits tumor progression, including proliferation and metastasis, and overexpression of TDP43 promotes proliferation and malignancy of mammary epithelial cells...
March 26, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29515366/the-activating-transcription-factor-3-atf3-homozygous-knockout-mice-exhibit-enhanced-conditioned-fear-and-down-regulation-of-hippocampal-gelsolin
#3
Chia-Sheng Pai, Pranao K Sharma, Hsien-Ting Huang, Srivaishnavi Loganathan, Heng Lin, Yu-Luan Hsu, Sarayut Phasuk, Ingrid Y Liu
The genetic and molecular basis underlying fear memory formation is a key theme in anxiety disorder research. Because activating transcription factor 3 ( ATF3 ) is induced under stress conditions and is highly expressed in the hippocampus, we hypothesize that ATF3 plays a role in fear memory formation. We used fear conditioning and various other paradigms to test Atf3 knockout mice and study the role of ATF3 in processing fear memory. The results demonstrated that the lack of ATF3 specifically enhanced the expression of fear memory, which was indicated by a higher incidence of the freeze response after fear conditioning, whereas the occurrence of spatial memory including Morris Water Maze and radial arm maze remained unchanged...
2018: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29507685/numb-and-numbl-differences-in-gene-regulation
#4
José Manuel García-Heredia, Amancio Carnero
NUMB, and its close homologue NUMBL, behave as tumor suppressor genes by regulating the Notch pathway. The downregulation of these genes in tumors is common, allowing aberrant Notch pathway activation and tumor progression. However, some known differences between NUMB and NUMBL have raised unanswered questions regarding the redundancy and/or combined regulation of the Notch pathway by these genes during the tumorigenic process. We have found that NUMB and NUMBL exhibit mutual exclusivity in human tumors, suggesting that the associated tumor suppressor role is regulated by only one of the two proteins in a specific cell, avoiding duplicate signaling and simplifying the regulatory network...
February 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29496391/structure-of-lnx1-ubc13-ubiquitin-complex-reveals-the-role-of-additional-motifs-for-the-e3-ligase-activity-of-lnx1
#5
Digant Nayak, J Sivaraman
LNX1 (Ligand of Numb Protein-X 1) is a RING and PDZ domain-containing E3 ubiquitin ligase that ubiquitinates human c-Src kinase. Here, we report the identification and structure of the ubiquitination domain of LNX1, the identification of Ubc13/Ube2V2 as a functional E2 in vitro, and the structural and functional studies of the Ubc13~Ub intermediate in complex with the ubiquitination domain of LNX1. The RING domain of LNX1 is embedded between two zinc-finger motifs (Zn-RING-Zn), both of which are crucial for its ubiquitination activity...
February 26, 2018: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29467404/basal-condensation-of-numb-and-pon-complex-via-phase-transition-during-drosophila-neuroblast-asymmetric-division
#6
Zelin Shan, Yuting Tu, Ying Yang, Ziheng Liu, Menglong Zeng, Huisha Xu, Jiafu Long, Mingjie Zhang, Yu Cai, Wenyu Wen
Uneven distribution and local concentration of protein complexes on distinct membrane cortices is a fundamental property in numerous biological processes, including Drosophila neuroblast (NB) asymmetric cell divisions and cell polarity in general. In NBs, the cell fate determinant Numb forms a basal crescent together with Pon and is segregated into the basal daughter cell to initiate its differentiation. Here we discover that Numb PTB domain, using two distinct binding surfaces, recognizes repeating motifs within Pon in a previously unrecognized mode...
February 21, 2018: Nature Communications
https://www.readbyqxmd.com/read/29450990/splicing-site-recognition-by-synergy-of-three-domains-in-splicing-factor-rbm10
#7
Pedro Serrano, John A Hammond, Michael Geralt, Kurt Wüthrich
Splicing factor RBM10 and its close homologues RBM5 and RBM6 govern the splicing of oncogenes such as Fas, NUMB, and Bcl-X. The molecular architecture of these proteins includes zinc fingers (ZnFs) and RNA recognition motifs (RRMs). Three of these domains in RBM10 that constitute the RNA binding part of this splicing factor were found to individually bind RNAs with micromolar affinities. It was thus of interest to further investigate the structural basis of the well-documented high-affinity RNA recognition by RMB10...
February 16, 2018: Biochemistry
https://www.readbyqxmd.com/read/29438128/toxins-in-pain
#8
Fernanda C Cardoso, Mahadhi Hasan, Tianjiao Zhao, Richard J Lewis
PURPOSE OF REVIEW: Pain is a distressing protective sensory experience warning of actual or potential tissue damage. Natural toxins have evolved to exploit pain and related neuronal pathways to facilitate prey capture and for defence, often producing either numbness, paralysis or intense pain by selectively modulating ion channels and receptors in pain pathways. Understanding how toxins modulate pain pathways can enhance our understanding of the physiological and pathological basis of pain...
February 12, 2018: Current Opinion in Supportive and Palliative Care
https://www.readbyqxmd.com/read/29412114/caveolin-1-in-stroke-neuropathology-and-neuroprotection-a-novel-molecular-therapeutic-target-for-ischemic-related-injury
#9
Shanshan Wang, Brian P Head
Cardiovascular disease and associated cerebral stroke are a global epidemic attributed to genetic and epigenetic factors, such as diet, life style and an increasingly sedentary existence due to technological advances in both the developing and developed world. There are approximately 5.9 million stroke-related deaths worldwide annually. Current epidemiological data indicate that nearly 16.9 million people worldwide suffer a new or recurrent stroke yearly. In 2014 alone, 2.4% of adults in the United States (U...
February 5, 2018: Current Vascular Pharmacology
https://www.readbyqxmd.com/read/29399185/il-8-is-upregulated-in-cervical-cancer-tissues-and-is-associated-with-the-proliferation-and-migration-of-hela-cervical-cancer-cells
#10
Linlin Jia, Fengying Li, Mingliang Shao, Wei Zhang, Chunbin Zhang, Xiaolian Zhao, Haiyan Luan, Yaling Qi, Pengxia Zhang, Lichun Liang, Xiuyue Jia, Kun Zhang, Yan Lu, Zhe Yang, Xiulin Zhu, Qi Zhang, Jiwei Du, Weiqun Wang
Interleukin-8 (IL-8) serves an important function in chronic inflammation and cancer development; however, the underlying molecular mechanism(s) of IL-8 in uterine cervical cancer remains unclear. The present study investigated whether IL-8 and its receptors [IL-8 receptor (IL-8R)A and IL-8RB] contributed to the proliferative and migratory abilities of HeLa cervical cancer cells, and also investigated the potential underlying molecular mechanisms. Results demonstrated that IL-8 and its receptors were detected in HeLa cells, and levels of IL-8RA were significantly increased compared with those of IL-8RB...
January 2018: Oncology Letters
https://www.readbyqxmd.com/read/29398419/the-endometrial-stem-cell-markers-notch-1-and-numb-are-associated-with-endometriosis
#11
Andreas N Schüring, Beatrice Dahlhues, Anna Korte, Ludwig Kiesel, Ulf Titze, Birthe Heitkötter, Christian Ruckert, Martin Götte
Previous studies reported increased expression of the notch pathway-associated protein Musashi-1 in endometriosis. This case-control study investigates an association of the endometrial stem cell markers notch-1 and numb with endometriosis. Fifty-one endometriosis patients and 76 controls were recruited in the IVF unit and tertiary endometriosis referral centre of a university hospital. All subjects underwent transcervical endometrial biopsy and diagnostic laparoscopy. Expression of endometrial notch-1 and numb was assessed by immunostaining and correlated with clinical data...
March 2018: Reproductive Biomedicine Online
https://www.readbyqxmd.com/read/29390306/syphilis-of-the-lumbar-spine-a-case-report-and-review-of-the-literature
#12
Ruofeng Yin, Liping Wang, Tinglong Zhang, Baolin Zhao
RATIONALE: Tertiary syphilis can manifest as gummatous disease, but gumma of the spine has been extremely rarely reported. PATIENT CONCERNS: A 61-year-old male complained of worsening pain and numbness in both lower legs for four weeks. DIAGNOSES: Syphilis of the Lumbar Spine. INTERVENTIONS: Pedicle screw fixation (L3-S1) and posterior decompression of the vertebral canal at L4-5 were performed. OUTCOMES: The postoperative VAS score of both lower extremities decline to 2 from 7 at admission...
December 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29382713/structural-determinants-controlling-14-3-3-recruitment-to-the-endocytic-adaptor-numb-and-dissociation-of-the-numb-%C3%AE-adaptin-complex
#13
Xing Chen, Ziheng Liu, Zelin Shan, Weiyi Yao, Aihong Gu, Wenyu Wen
Traffic of cargo across membranes helps establish, maintain, and reorganize distinct cellular compartments and is fundamental to many metabolic processes. The cargo-selective endocytic adaptor Numb participates in clathrin-dependent endocytosis by attaching cargoes to the clathrin adaptor α-adaptin. The phosphorylation of Numb at Ser-265 and Ser-284 recruits the regulatory protein 14-3-3, accompanied by the dissociation of Numb from α-adaptin and Numb's translocation from the cortical membrane to the cytosol...
January 30, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29362432/nrf2-antioxidant-pathway-suppresses-numb-mediated-epithelial-mesenchymal-transition-during-pulmonary-fibrosis
#14
Zhihui Zhang, Jiao Qu, Cheng Zheng, Panpan Zhang, Wencheng Zhou, Wenhui Cui, Xiaoting Mo, Liucheng Li, Liang Xu, Jian Gao
Epithelial mesenchymal transition (EMT) is a key progression that promotes pulmonary fibrosis (PF). Numb, a phosphotyrosine-binding domain (PTB) protein, is implicated with EMT. Nuclear factor erythroid 2-related factor2 (Nrf2) and its downstream proteins heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) constitute an important pathway of antioxidant defense signal for protecting against PF. It remains elusive whether Nrf2 antioxidant pathway and Numb have a potential relationship in EMT-mediated PF...
January 23, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29339436/rewired-notch-p53-by-numb-ing-mdm2
#15
Hyungsoo Kim, Ze'ev A Ronai
Although numerous pathways are known to control the tumor suppressor protein p53, coordinated regulation of the p53-Notch axis by Numb may have an even more remarkable impact. In this issue, Colaluca at al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201709092) reveal an unexpected role of a newly characterized Numb splice variant in the regulation of p53, which may have significant implications for therapeutic intervention in breast cancer.
February 5, 2018: Journal of Cell Biology
https://www.readbyqxmd.com/read/29333723/nandrolone-induced-nuclear-accumulation-of-myod-protein-is-mediated-by-numb-a-notch-inhibitor-in-c2c12-myoblasts
#16
Xin-Hua Liu, Rita De Gasperi, William A Bauman, Christopher P Cardozo
Signaling via the androgen receptor (AR) stimulates myogenic progenitor differentiation. In addition, myogenic differentiation factor D (MyoD) and Numb, a Notch inhibitor, play key roles in regulating myogenic differentiation. Nandrolone, an anabolic steroid, upregulates both MyoD and Numb expression in myogenic cells. However, the molecular mechanisms by which MyoD is upregulated by nandrolone are unclear. Moreover, the potential crosstalk between nandrolone, MyoD, and Numb is not well understood. With these considerations in mind, we examined the effects of nandrolone on the expression of MyoD mRNA and protein, and determined the interactions of MyoD and Numb in the presence or absence of nandrolone in differentiating C2C12 myoblasts...
January 2018: Physiological Reports
https://www.readbyqxmd.com/read/29295957/the-depalmitoylase-apt1-directs-the-asymmetric-partitioning-of-notch-and-wnt-signaling-during-cell-division
#17
Ewa Stypulkowski, Irfan A Asangani, Eric S Witze
Asymmetric cell division results in two distinctly fated daughter cells. A molecular hallmark of asymmetric division is the unequal partitioning of cell fate determinants. We have previously established that growth factor signaling promotes protein depalmitoylation to foster polarized protein localization, which, in turn, drives migration and metastasis. We report protein palmitoylation as a key mechanism for the asymmetric partitioning of the cell fate determinants Numb and β-catenin through the activity of the depalmitoylating enzyme APT1...
January 2, 2018: Science Signaling
https://www.readbyqxmd.com/read/29290973/human-oncoprotein-musashi-2-n-terminal-rna-recognition-motif-backbone-assignment-and-identification-of-rna-binding-pocket
#18
Lan Lan, Minli Xing, Justin T Douglas, Philip Gao, Robert P Hanzlik, Liang Xu
RNA-binding protein Musashi-2 (MSI2) is a key regulator in stem cells, it is over-expressed in a variety of cancers and its higher expression is associated with poor prognosis. Like Musashi-1, it contains two N-terminal RRMs (RNA-recognition Motifs, also called RBDs (RNA-binding Domains)), RRM1 and RRM2, which mediate the binding to their target mRNAs. Previous studies have obtained the three-dimensional structures of the RBDs of Musashi-1 and the RBD1:RNA complex. Here we show the binding of MSI2-RRM1 to a 15nt Numb RNA in Fluorescence Polarization assay and time resolved Fluorescence Resonance Energy Transfer assay...
December 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/29279594/poems-syndrome
#19
W W T Nyunt, R Remli, F A Abdul Muttlib, C F Leong, N Masir, N R Tumian, S F S Abdul Wahid
POEMS syndrome is the syndrome of Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein and typical Skin changes. A 65-year-old lady presented with the 2-day-history of inability to walk, 4-month-history of progressive worsening of muscle weakness of both lower limbs and 1-year-history of progressive worsening of bilateral numbness of lower limbs. Nerve conduction study revealed generalized sensorimotor demyelinating polyneuropathy. She was initially treated as chronic inflammatory demyelinating polyradiculoneuropathy with intravenous immunoglobulin (IVIG) and high-dose prednisolone...
December 2017: Malaysian Journal of Pathology
https://www.readbyqxmd.com/read/29230425/neuroprotective-potential-of-gentongping-in-rat-model-of-cervical-spondylotic-radiculopathy-targeting-ppar-%C3%AE-pathway
#20
Wen Sun, Kang Zheng, Bin Liu, Danping Fan, Hui Luo, Xiaoyuan Qu, Li Li, Xiaojuan He, Jianfeng Yi, Cheng Lu
Cervical spondylotic radiculopathy (CSR) is the most general form of spinal degenerative disease and is characterized by pain and numbness of the neck and arm. Gentongping (GTP) granule, as a classical Chinese patent medicine, has been widely used in curing CSR, whereas the underlying mechanism remains unclear. Therefore, the aim of this study is to explore the pharmacological mechanisms of GTP on CSR. The rat model of CSR was induced by spinal cord injury (SCI). Our results showed that GTP could significantly alleviate spontaneous pain as well as ameliorate gait...
2017: Journal of Immunology Research
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