DOCSLIB.ORG

Induction of Differentiation by Regulating the Musashi/Numb/Notch Pathway

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Induction of Differentiation by Regulating the Musashi/Numb/Notch Pathway Cell Research (2010) 20:1083-1085. npg © 2010 IBCB, SIBS, CAS All rights reserved 1001-0602/10 $ 32.00 RESEARCH HIGHLIGHT www.nature.com/cr New insight into cancer therapeutics: Induction of differentiation by regulating the Musashi/Numb/Notch pathway Yoshinori Nishimoto1, Hideyuki Okano1 1Department of Physiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan Cell Research (2010) 20:1083-1085. doi:10.1038/cr.2010.122; published online 31 August 2010 The Musashi (Msi) family is a group lular Notch signaling, by binding to cells” which expands to some kinds of of RNA-binding proteins characterized the 3′ untranslated region (UTR) of the solid tumors [10]. Then, Msi1 could by two RNA recognition motifs (RRMs) Numb mRNA [8]. Activation of Notch be a versatile marker of “cancer stem and is evolutionarily conserved [1, 2]. signaling induces the transactivation of cells” especially during an early phase In mammals, two isoforms of this fam- the promoter of the Hes-1 gene (Figure with strong proliferative activities. This ily, Msi1 and Msi2, are co-expressed in 1). The activation of Notch-pathway suggests the possibility that Msi1 might neural precursor cells, including neural is known to regulate the self-renewal have some important roles as a trigger stem cells (NSCs). Msi2 exhibits high of NSCs positively [9]. Previously, of proliferative switching from differ- sequence homology with Msi1, which our laboratory reported that Msi1 and entiated state to cancer production in a is more than 90% at the amino acid Msi2 developmentally controlled self- reverse direction to development. level within the RNA-binding domain. renewal of embryonic cells, as well as Although a previous report showed Msi2 is transcribed over the tissues of adult CNS stem/progenitor cells [6]. that Msi2 gene was rearranged to form ubiquitously [3] in contrast with Msi1 Based on the evidence that tissue stem a Msi2/HoxA9 fusion gene in a chronic enrichment in neural stem cells or pro- cells exist in many adult tissues, includ- myeloid leukemia (CML) case with genitor cells of the peri-ventricular area ing the hematopoietic system, intestine, the 7p15 breakpoint [14], the recent in the embryonic [4] and postnatal [5] mammary gland, testis, skeletal muscle, papers reported by Ito et al. [12] and mammalian brains. When both Msi1 skin, hair follicle and myocardium, oth- Kharas et al. [13] were the first re- and Msi2 genes were knocked-out, er than the CNS and neural crest-derived ports to show clearly the relationship neurosphere formation was markedly tissue, Msi/Numb/Notch signaling is between Msi2-inducing pathway and inhibited; however, single knockout did considered to be associated with many hematopoietic malignancy. These two not bring about such disturbance [6]. adult malignancies [2]. In fact, not only reports suggested a new strategy for the Originally, Msi was identified as a at the normal developmental stages, the therapy of aggressive leukemia. Using required factor for the asymmetric cell Msi-signaling pathway is also reported the in vivo models of CML in a chronic division of the sensory organ precursor to work during tumorigenesis in several phase and in an aggressive blast phase cell (SOP) of the Drosophila adult ex- adult tissues, including glioblastoma [15], it was proposed that Msi2-Numb ternal sensory organ [7]. In mammals, and esophageal, colon, pulmonary, pathway should control the differentia- the function of Msi has been, thus mammary and bladder carcinomas tion of CML cells and that this pathway far, found to activate Notch signaling [2, 10-13]. Intriguingly, in the case of could be the novel target of leukemia through the translational repression of esophageal adenocarcinoma, Msi1 ex- treatment [12]. NUMB, which represses an intracel- pression was the highest in glands dur- Ito et al. first asked whether the levels ing early cancer development. In con- of MSI/NUMB expression and Notch trast, Msi1 level become weaker when signaling altered in the CML model Correspondence: Hideyuki Okano esophageal adenocarcinoma grows into mice [12]. Myeloid blast crisis was Tel: +81-3-5363-3747; Fax: +81-3-3357-5445 E-mail: [email protected], hidokano@ the advanced stage. Such findings have modeled by transplanting hematopoietic a2.keio.jp advocated a concept of “cancer stem stem cells (HSCs)-enriched KLS cells, npg 1084 which was transduced with Bcr-Abl Msi2 gene. Nup98-HoxA9 transduced creased amount of NUMB protein in the and Nup98-HoxA9. HOXA9 regulates with retroviral vector along with Bcr- LAMA-84 cell lines, derived from the expression of many genes that are Abl could overexpress the Msi2 gene blast crisis CML patient, was observed implicated in hematopoiesis and in in KLS cells and upregulation of MSI2 with immunoblot. tumorigenesis. Using the established expression led to downregulation of Then, Ito et al. asked whether hu- mouse model representing chronic NUMB (Figure 1). At the same time, man leukemia in blast crisis showed phase and myeloid blast crisis CML Kharas et al. established doxycycline- aberrant up-regulation of Msi2 as well. (initiated by the Bcr-Abl translocation inducible Msi2 expression systems both Analysis of samples from 30 Korean and progressed by Nup98-HoxA9 ex- in vitro and in vivo, which culminated and British patients showed significant pression) [16], they found Numb was in hematopoietic colony-forming with higher levels of Msi2 gene expression expressed at significantly lower levels more immature myeloid phenotype in in blast crisis CML. As predicted from and Msi2 was particularly elevated in vitro and expansion of hematopoietic the CML mice model, microarray data the blast crisis phase. Notably, Msi2 stem cells (HSCs) and short-term pro- of 90 samples from banks in the United was expressed at higher levels than genitor cells in vivo [13]. They also States showed elevated levels of Msi2, Msi1 in the CML mice model, especially transduced doxycycline-inducible Msi2 HoxA9 and Hes1 and decrement of in hematopoietic stem cell-enriched cells with the Bcr-Abl oncogene and Numb among most of CML patients in populations including KLS cells and transplanted them into mice. Consistent the blast crisis phase. Similarly, Kharas the lineage-negative fraction of blast with the other report, Msi2 induced im- et al. [13] showed the increased level crisis CML. Moreover, they identified mature myeloid leukemia that mimicked of Msi2 and decreased level of Numb a putative HoxA9-binding element CML blastic crisis phase. Conversely, from 33 samples of myeloid blast at the position –5.7 kb in the murine when Msi2 was knocked down, an in- crisis by comparing with 57 samples of chronic phase CML obtained in the United States. It is particularly noteworthy that Ito et al. suggested the apparent clues B Musashi 2 suppressing tumor growth and mortal- HoxA9 –5.7 kb ity rates in the established CML model A NOTCH mice in vivo. They showed that a higher Numb expression made leukemia more MUSASHI2 D AAAAA differentiated and unable to propagate C Numb mRNA disease markedly. In fact, transplanta- (Suppressed translation) Trib2 Hes1 tion of cells expressing Numb decreased the frequency of developing leukemia in the model mice, from 83% to 63%. Chronic phase Blast crisis phase E When the authors transplanted cells Proliferation transfected with Numb, from primary transplanted mice for donor-derived cells, into irradiated recipient second- Differentiation ary mice, the survival rate to evaluate propagation of disease was elevated compared to the control, from 20% Figure 1 Scheme of the CML state in an aggressive blast crisis phase. In to 93%. These results showed that the chronic phase, Numb blocks activation of the Notch signaling (A). During hu- elevated levels of NUMB can inhibit man CML progression, the following changes occurs; Nup98-HoxA9 oncogene disease progression. Additionally, us- binds the putative element at 5.7 kb upstream of transcription start site to trig- ing gene-trap mutants or short hairpin ger the upregulated expression of Musashi2 gene (B). The elevated level of RNA approach, loss of Msi2 impaired MUSASHI2 leads to the downregulation of NUMB, by binding to the 3′ UTR of leukemia growth and increased survival Numb mRNA to inhibit translation (C). Inhibition of Notch signaling is cancelled rates significantlyin vivo, especially in by suppression of NUMB (D), leading to the elevated expression of the targets, blast crisis CML. Similar to NUMB Hes1 gene and Trib2 gene. A series of these activation cause proliferative change from chronic phase to blast crisis phase of CML (E). Red symbols and induction, Msi2-shRNA induced the letters represent increased level of each factor and enhanced activation (or in- differentiation of leukemic cells and in- hibition) in blast crisis phase CML. hibited their propagating ability [12]. Cell Research | Vol 20 No 10 | October 2010 npg 1085 Ito et al. also reported the association References Notch pathway molecules are essential of Msi2 with high risk of relapse after for the maintenance, but not the gener- ation, of mammalian neural stem cells. allogeneic transplantation and poorer 1 Okano H, Imai T, Okabe M. Musashi: Genes Dev 2002; 16:846-858. outcomes, indicating the possibility to a translational regulator of cell fates. J 10 Bobryshev YV, Freeman AK, Botelho Cell Sci 2002; 115(Pt 7):1355-1359. make use of MSI2 as an early marker NK, et al. Expression of the putative 2 Okano H, Kawahara H, Toriya M, Na- of advanced CML. On the other hand, stem cell marker Musashi-1 in Barrett's kao K, Shibata S, Imai T. Function of Kharas et al. confirmed that Msi2 ex- esophagus and esophageal adenocarci- RNA-binding protein Musashi-1 in noma. Dis Esophagus 2010 Apr 29. doi: pression had relevance to poor clinical stem cells. Exp Cell Res 2005; 306:349- 10.1111/j.1442-2050.2010.01061.x prognosis among at least congeni- 356.
Load more

Recommended publications
  • Mdm2-Mediated Ubiquitylation: P53 and Beyond
    Cell Death and Differentiation (2010) 17, 93–102 & 2010 Macmillan Publishers Limited All rights reserved 1350-9047/10 $32.00 www.nature.com/cdd Review Mdm2-mediated ubiquitylation: p53 and beyond J-C Marine*,1 and G Lozano2 The really interesting genes (RING)-finger-containing oncoprotein, Mdm2, is a promising drug target for cancer therapy. A key Mdm2 function is to promote ubiquitylation and proteasomal-dependent degradation of the tumor suppressor protein p53. Recent reports provide novel important insights into Mdm2-mediated regulation of p53 and how the physical and functional interactions between these two proteins are regulated. Moreover, a p53-independent role of Mdm2 has recently been confirmed by genetic data. These advances and their potential implications for the development of new cancer therapeutic strategies form the focus of this review. Cell Death and Differentiation (2010) 17, 93–102; doi:10.1038/cdd.2009.68; published online 5 June 2009 Mdm2 is a key regulator of a variety of fundamental cellular has also emerged from recent genetic studies. These processes and a very promising drug target for cancer advances and their potential implications for the development therapy. It belongs to a large family of (really interesting of new cancer therapeutic strategies form the focus of this gene) RING-finger-containing proteins and, as most of its review. For a more detailed discussion of Mdm2 and its other members, Mdm2 functions mainly, if not exclusively, as various functions an interested reader should also consult an E3 ligase.1 It targets various substrates for mono- and/or references9–12. poly-ubiquitylation thereby regulating their activities; for instance by controlling their localization, and/or levels by The p53–Mdm2 Regulatory Feedback Loop proteasome-dependent degradation.
    [Show full text]
  • Novel Mechanisms of Spinal Cord Plasticity in a Mouse Model of Motoneuron Disease
    Hindawi Publishing Corporation BioMed Research International Volume 2015, Article ID 654637, 10 pages http://dx.doi.org/10.1155/2015/654637 Research Article Novel Mechanisms of Spinal Cord Plasticity in a Mouse Model of Motoneuron Disease Rosario Gulino,1,2 Rosalba Parenti,1 and Massimo Gulisano1 1 Department of Biomedical and Biotechnological Sciences, University of Catania, Via Santa Sofia 64, 95127 Catania, Italy 2IOM Ricerca s.r.l., Via Penninazzo 11, 95029 Viagrande, Italy Correspondence should be addressed to Rosario Gulino; [email protected] Received 26 September 2014; Accepted 16 December 2014 Academic Editor: Andrea Vecchione Copyright © 2015 Rosario Gulino et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. A hopeful spinal cord repairing strategy involves the activation of neural precursor cells. Unfortunately, their ability to generate neurons after injury appears limited. Another process promoting functional recovery is synaptic plasticity. We have previously studied some mechanisms of spinal plasticity involving BDNF, Shh, Notch-1, Numb, and Noggin, by using a mouse model of motoneuron depletion induced by cholera toxin-B saporin. TDP-43 is a nuclear RNA/DNA binding protein involved in amyotrophic lateral sclerosis. Interestingly, TDP-43 could be localized at the synapse and affect synaptic strength. Here, we would like to deepen the investigation of this model of spinal plasticity. After lesion, we observed a glial reaction and an activity-dependent modification of Shh, Noggin, and Numb proteins. By using multivariate regression models, we found that Shh and Noggin could affect motor performance and that these proteins could be associated with both TDP-43 and Numb.
    [Show full text]
  • 1 Small-Molecule Targeting of MUSASHI RNA-Binding Activity in Acute Myeloid Leukemia 2 3 Gerard Minuesa1, Steven K
    bioRxiv preprint doi: https://doi.org/10.1101/321174; this version posted May 14, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia 2 3 Gerard Minuesa1, Steven K. Albanese2,3, Arthur Chow1, Alexandra Schurer1, Sun-Mi Park1, 4 Christina Z. Rotsides4, James Taggart1, Andrea Rizzi3,5, Levi N. Naden3, Timothy Chou1, Saroj 5 Gourkanti1, Daniel Cappel6, Maria C. Passarelli3,7, Lauren Fairchild3,8, Carolina Adura9, J Fraser 6 Glickman9, Jessica Schulman10, Christopher Famulare11, Minal Patel11, Joseph K. Eibl12, Gregory 7 M. Ross12, Derek Tan4, Christina Leslie3, Thijs Beuming13, Yehuda Goldgur14, John D. Chodera3, 8 Michael G. Kharas1,* 9 10 1. Molecular Pharmacology Program, Experimental Therapeutics Center and Center for Stem 11 Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA 12 2. Louis V. Gerstner Jr. Graudate School of Biomedical Sciences, Memorial Sloan Kettering 13 Cancer Center, New York, NY, 10065, USA 14 3. Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan 15 Kettering Cancer Center, New York, NY, 10065, USA 16 4. Chemical Biology Program and Tri-Institutional Research Program, Memorial Sloan Kettering 17 Cancer Center, 1275 York Avenue, Box 422, New York, New York, NY, 10065, USA 18 5. Tri-Institutional Training Program in Computational Biology and Medicine, New York, NY, 19 10065, USA 20 6. Schrödinger GmbH, Q7, 23, 68161 Mannheim, Germany 21 7. Weill Cornell Medical College, Rockefeller University & Sloan Kettering Institute Tri-Institutional 22 MD-PhD Program, New York, NY, 10065, USA 23 8.
    [Show full text]
  • Musashi RNA-Binding Proteins As Cancer Drivers and Novel Therapeutic Targets Alexander E
    Published OnlineFirst January 31, 2017; DOI: 10.1158/1078-0432.CCR-16-2728 Review Clinical Cancer Research Musashi RNA-Binding Proteins as Cancer Drivers and Novel Therapeutic Targets Alexander E. Kudinov1, John Karanicolas1, Erica A. Golemis1, and Yanis Boumber1,2 Abstract Aberrant gene expression that drives human cancer can arise mRNA stability and translation of proteins operating in essential from epigenetic dysregulation. Although much attention has oncogenic signaling pathways, including NUMB/Notch, PTEN/ focused on altered activity of transcription factors and chroma- mTOR, TGFb/SMAD3, MYC, cMET, and others. On the basis of tin-modulating proteins, proteins that act posttranscriptionally these activities, MSI proteins maintain cancer stem cell popula- can potently affect expression of oncogenic signaling proteins. tions and regulate cancer invasion, metastasis, and development The RNA-binding proteins (RBP) Musashi-1 (MSI1) and Musashi- of more aggressive cancer phenotypes, including drug resistance. 2 (MSI2) are emerging as regulators of multiple critical biological Although RBPs are viewed as difficult therapeutic targets, initial processes relevant to cancer initiation, progression, and drug efforts to develop MSI-specific inhibitors are promising, and RNA resistance. Following identification of Musashi as a regulator of interference–based approaches to inhibiting these proteins have progenitor cell identity in Drosophila, the human Musashi proteins had promising outcomes in preclinical studies. In the interim, were initially linked to control of maintenance of hematopoietic understanding the function of these translational regulators may stem cells, then stem cell compartments for additional cell types. yield insight into the relationship between mRNA expression and More recently, the Musashi proteins were found to be overex- protein expression in tumors, guiding tumor-profiling analysis.
    [Show full text]
  • NUMB and NUMBL Differences in Gene Regulation
    www.impactjournals.com/oncotarget/ Oncotarget, 2018, Vol. 9, (No. 10), pp: 9219-9234 Research Paper NUMB and NUMBL differences in gene regulation José Manuel García-Heredia1,2,3 and Amancio Carnero1,3 1Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain 2Department of Vegetal Biochemistry and Molecular Biology, University of Seville, Seville, Spain 3CIBER de Cáncer, Instituto de Salud Carlos III, Pabellón 11, Planta 0, Madrid, Spain Correspondence to: Amancio Carnero, email: [email protected] Keywords: NUMB; NUMBL; cancer; Notch pathway; WNT pathway Received: September 06, 2017 Accepted: January 03, 2018 Published: January 11, 2018 Copyright: García-Heredia et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT 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. We have also found differences in gene expression due to NUMB or NUMBL downregulation.
    [Show full text]
  • Identification and Preliminary Functional Analysis of Alternative Splicing of Siah1 in Xenopus Laevis
    Biochemical and Biophysical Research Communications 396 (2010) 419–424 Contents lists available at ScienceDirect Biochemical and Biophysical Research Communications journal homepage: www.elsevier.com/locate/ybbrc Identification and preliminary functional analysis of alternative splicing of Siah1 in Xenopus laevis Luan Wen a,b, Jiantao Liu a,c, Yonglong Chen a, Donghai Wu a,* a Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Road, Guangzhou Science Park, 510530 Guangzhou, China b Graduate University of Chinese Academy of Sciences, 100049 Beijing, China c Laboratory of Veterinary Pharmacology, College of Veterinary Medicine South China Agricultural University, Guangzhou, China article info abstract Article history: Siah proteins are vertebrate homologs of the Drosophila ‘seven in absentia’ gene. In this study, we char- Received 11 April 2010 acterized two splicing forms, Siah1a and Siah1b, of the Xenopus seven in absentia homolog 1 gene (Siah1). Available online 22 April 2010 Overexpression of xSiah1a led to severe suppression of embryo cleavage, while that of xSiah1b was not effective even at a high dose. Competition analysis demonstrated that co-expression of xSiah1a and 1b Keywords: generated the same phenotype as overexpression of xSiah1a alone, suggesting that xSiah1b does not Xenopus interfere with the function of xSiah1a. Since xSiah1b has an additional 31 amino acids in the N-terminus xSiah1a compared to xSiah1a, progressive truncation of xSiah1b from the N-terminus showed that inability of xSiah1b xSiah1b to affect embryo cleavage was associated with the length of the N-terminal extension of extra amino acids. The possible implication of this finding is discussed.
    [Show full text]
  • Numb−/Low Enriches a Castration-Resistant Prostate Cancer Cell Subpopulation Associated with Enhanced Notch and Hedgehog Signaling
    Published OnlineFirst July 27, 2017; DOI: 10.1158/1078-0432.CCR-17-0913 Biology of Human Tumors Clinical Cancer Research NumbÀ/low Enriches a Castration-Resistant Prostate Cancer Cell Subpopulation Associated with Enhanced Notch and Hedgehog Signaling Yanjing Guo1, Kai Zhang2, Chaping Cheng2, Zhongzhong Ji2, Xue Wang2, Minglei Wang1, Mingliang Chu1, Dean G. Tang3, Helen He Zhu1, and Wei-Qiang Gao1,2 Abstract Purpose: To elucidate the role and molecular mechanism of Results: We show here that Numb was downregulated and Numb in prostate cancer and the functional contribution of negatively correlated with prostate cancer advancement. Func- À Numb /low prostate cancer cells in castration resistance. tionally, Numb played an inhibitory role in xenograft prostate Experimental Design: The expression of Numb was assessed tumor growth and castration-resistant prostate cancer develop- using multiple Oncomine datasets and prostate cancer tissues ment by suppressing Notch and Hedgehog signaling. Using from both humans and mice. The biological effects of the a Numb promoter–based lentiviral reporter system, we were able À overexpression and knockdown of Numb in human prostate to distinguish Numb /low prostate cancer cells from Numbhigh À cancer cell lines were investigated in vitro and in vivo.In cells. Numb /low prostate cancer cells were smaller and quiescent, addition, we developed a reliable approach to distinguish preferentially expressed Notch and Hedgehog downstream and between prostate cancer cell populations with a high or low stem-cell–associated genes, and associated with a greater resis- endogenous expression of Numb protein using a Numb pro- tance to ADT. The inhibition of the Notch and Hedgehog signal- À moter–based lentiviral reporter system.
    [Show full text]
  • NUMB Enhances Notch Signaling by Repressing Ubiquitination of NOTCH1 Intracellular Domain
    doi:10.1093/jmcb/mjz088 Journal of Molecular Cell Biology (2020), 12(5), 345–358 | 345 Published online September 3, 2019 Article NUMB enhances Notch signaling by repressing ubiquitination of NOTCH1 intracellular domain Zhiyuan Luo†,LiliMu†, Yue Zheng, Wenchen Shen, Jiali Li, Lichao Xu, Bo Zhong, Ying Liu*, and Yan Zhou * College of Life Sciences, Renmin Hospital of Wuhan University, Medical Research Institute at School of Medicine, Wuhan University, Wuhan 430072, China † These authors contributed equally to this work. * Correspondence to: Ying Liu, E-mail: [email protected]; Yan Zhou, E-mail: [email protected] Edited by Zhen-Ge Luo The release and nuclear translocation of the intracellular domain of Notch receptor (NICD) is the prerequisite for Notch signaling- mediated transcriptional activation. NICD is subjected to various posttranslational modifications including ubiquitination. Here, we surprisingly found that NUMB proteins stabilize the intracellular domain of NOTCH1 receptor (N1ICD) by regulating the ubiquitin– proteasome machinery, which is independent of NUMB’s role in modulating endocytosis. BAP1, a deubiquitinating enzyme (DUB), was further identified as a positive N1ICD regulator, and NUMB facilitates the association between N1ICD and BAP1 to stabilize N1ICD. Intriguingly, BAP1 stabilizes N1ICD independent of its DUB activity but relying on the BRCA1-inhibiting function. BAP1 strengthens Notch signaling and maintains stem-like properties of cortical neural progenitor cells. Thus, NUMB enhances Notch signaling by regulating the ubiquitinating activity of the BAP1–BRCA1 complex. Keywords: NUMB, Notch intracellular domain, BAP1, ubiquitination, neural progenitor cells Introduction enzymes (DUBs) have been reported to regulate their turnover Diversifying cell fates during animal development requires and activities (Le Bras et al., 2011; Moretti and Brou, 2013).
    [Show full text]
  • Neurotrophins As Key Regulators of Cell Metabolism: Implications for Cholesterol Homeostasis
    International Journal of Molecular Sciences Review Neurotrophins as Key Regulators of Cell Metabolism: Implications for Cholesterol Homeostasis Mayra Colardo 1 , Noemi Martella 1, Daniele Pensabene 1, Silvia Siteni 2, Sabrina Di Bartolomeo 1 , Valentina Pallottini 3,4 and Marco Segatto 1,* 1 Department of Biosciences and Territory, University of Molise, Contrada Fonte Lappone, 86090 Pesche, Italy; [email protected] (M.C.); [email protected] (N.M.); [email protected] (D.P.); [email protected] (S.D.B.) 2 Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA; [email protected] 3 Department of Science, University Roma Tre, Viale Marconi 446, 00146 Rome, Italy; [email protected] 4 Neuroendocrinology Metabolism and Neuropharmacology Unit, IRCSS Fondazione Santa Lucia, Via del Fosso Fiorano 64, 00143 Rome, Italy * Correspondence: [email protected] Abstract: Neurotrophins constitute a family of growth factors initially characterized as predominant mediators of nervous system development, neuronal survival, regeneration and plasticity. Their biological activity is promoted by the binding of two different types of receptors, leading to the generation of multiple and variegated signaling cascades in the target cells. Increasing evidence indicates that neurotrophins are also emerging as crucial regulators of metabolic processes in both neuronal and non-neuronal cells. In this context, it has been reported that neurotrophins affect Citation: Colardo, M.; Martella, N.; redox balance, autophagy, glucose homeostasis and energy expenditure. Additionally, the trophic Pensabene, D.; Siteni, S.; Di support provided by these secreted factors may involve the regulation of cholesterol metabolism. In Bartolomeo, S.; Pallottini, V.; Segatto, this review, we examine the neurotrophins’ signaling pathways and their effects on metabolism by M.
    [Show full text]
  • The Musashi Family RNA-Binding Proteins in Stem Cells
    Article in press - uncorrected proof BioMol Concepts, Vol. 1 (2010), pp. 59–66 • Copyright ᮊ by Walter de Gruyter • Berlin • New York. DOI 10.1515/BMC.2010.005 Review The Musashi family RNA-binding proteins in stem cells Kenichi Horisawa1, Takao Imai2, Hideyuki Okano2 mRNA, causing asymmetric cell division (6, 7). Thereafter, and Hiroshi Yanagawa1,* its mammalian homologs, Musashi1 (Msi1) and Musashi2 (Msi2), were found in mice (8, 9). Many Musashi and 1 Department of Biosciences and Informatics, Faculty of Musashi-like proteins have since been discovered in various Science and Technology, Keio University, 3-14-1 Hiyoshi, multicellular animals, and overall the primary structure and Kohoku-ku, Yokohama 223-8522, Japan expression pattern are highly conserved among them 2 Department of Physiology, Keio University School of (10–16). Strong expression of Msi1 protein was observed in Medicine, Shinjuku, Tokyo 160-8582, Japan the nervous systems of vertebrates (17). In the central nerv- * Corresponding author ous system (CNS) of mouse, Msi1 protein is expressed in e-mail: [email protected] undifferentiated neural stem/precursor cells (NS/PCs) at the embryonic and adult stages (8, 17, 18). Molecular biological studies revealed that in mouse Msi1 in these cells controls Abstract the Notch signaling pathway through translational reduction The Musashi family is an evolutionarily conserved group of of the m-Numb protein, an inhibitor of the Notch pathway, RNA-binding proteins. In mammal, two members of the and thereby maintains the stem/progenitor cell status (19). group, Msi1 and Msi2, have been identified to date. Msi1 is Interestingly, expression of Msi1 was also observed in many considered to play roles in maintaining the stem cell status types of somatic stem cells in adult tissues, e.g., eye (20), (stemness) of neural stem/progenitor cells in adults and in intestine (21), stomach (22), mammary gland (23), and hair the development of central nervous system through transla- follicle (24).
    [Show full text]
  • Computational Approach to Identify Mutations in Genes of Notch Signaling Pathway and Its Association with OSCC
    Journal of Pharmaceutical Research International 32(20): 84-92, 2020; Article no.JPRI.59681 ISSN: 2456-9119 (Past name: British Journal of Pharmaceutical Research, Past ISSN: 2231-2919, NLM ID: 101631759) Computational Approach to Identify Mutations in Genes of Notch Signaling Pathway and Its Association with OSCC Madhumithaa Sivarajan1, A. S. Smiline Girija2, A. Paramasivam3 and J. Vijayashree Priyadharsini3* 1Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, India. 2Department of Microbiology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, 162 , Poonamallee High Road, Chennai 600077, Tamil Nadu, India. 3Biomedical Research Unit and Laboratory Animal Centre-Dental Research Cell, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai 600077, India. Authors’ contributions This work was carried out in collaboration among all authors. Author JVP designed the study, performed the statistical analysis, wrote the protocol and wrote the first draft of the manuscript. Authors ASSG and AP managed the analyses of the study. Author MS managed the literature searches and certain computational analysis. All authors read and approved the final manuscript. Article Information DOI: 10.9734/JPRI/2020/v32i2030732 Editor(s): (1) Dr. Mohamed Fawzy Ramadan Hassanien, Zagazig University, Egypt. Reviewers: (1) Mustika Tuwo, Hasanuddin University, Indonesia. (2) Maysaa
    [Show full text]
  • REVIEW Cell and Molecular Biology of Notch
    459 REVIEW Cell and molecular biology of Notch Ulla-Maj Fiu´za and Alfonso Martinez Arias Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK (Correspondence should be addressed to U-M Fiu´za; Email: [email protected]) Abstract Notch signalling is a cell–cell communication process, which complexity which could account for the multitude of roles it has allows the establishment of patterns of gene expression and during development and in adult organisms. In this review, we differentiation, regulates binary cell fate choice and the will describe the multiple roles of Notch and how various factors maintenance of stem cell populations. So far, the data published can regulate Notch signalling. has elucidated the main players in the Notch signalling pathway. Journal of Endocrinology (2007) 194, 459–474 However, its regulatory mechanisms are exhibiting an increasing The structure of Notch and the Notch signalling which allowed the discovery of a core set of molecules involved pathway in Notch signalling and lead to the understanding of how they organize into a signalling pathway. The Notch genes encode members of a family of receptors that In mammals, there are four Notch genes and five genes mediate short-range signalling events. A prototypical Notch encoding ligands, three Delta-like and two Jagged (Fig. 1). In gene encodes a single transmembrane receptor composed in Drosophila, there is only one Notch-encoding gene, one Delta its extracellular region of a conserved array of up to 36 and one Jagged homologue (Serrate; Maine et al. 1995, epidermal growth factor (EGF)-like repeats, involved in Lissemore & Starmer 1999).
    [Show full text]