DOCSLIB.ORG

Numb−/Low Enriches a Castration-Resistant Prostate Cancer Cell Subpopulation Associated with Enhanced Notch and Hedgehog Signaling

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read 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. The difference between ing pathways significantly increased apoptosis in Numb /low À Numb /low and Numbhigh prostate cancer cells in the response cells in response to ADT. À to androgen-deprivation therapy (ADT) was then tested. Conclusions: Numb /low enriches a castration-resistant The likely downstream factors of Numb were analyzed using prostate cancer cell subpopulation that is associated with luciferase reporter assays, immunoblotting, and quantitative unregulated Notch and Hedgehog signaling. Clin Cancer Res; real-time PCR. 1–13. Ó2017 AACR. Introduction standing of the molecular etiology of castration resistance remains limited, leading to limited intervention approaches The most recent statistics suggest that aging and a Western- for the treatment of this deadly disease. In addition, prostate ized lifestyle are associated with an increasing trend of prostate cancer cells display great intratumor heterogeneity. Their cancer incidence and mortality rates worldwide (1, 2). Andro- response to androgen deprivation therapy is also radically gen deprivation therapy in conjunction with surgery or radia- different from each other (4–6). The targeted eradication of tion is the mainstream treatment strategy for advanced prostate cell subpopulations with greater castration resistance may serve cancers (3). However, the emergence of castration-resistant as an optimal strategy for the treatment of CRPC. The identi- prostate cancer (CRPC) remains the predominant cause of fication of those cell subpopulations and the understanding death in prostate cancer patients. Unfortunately, our under- of their molecular characteristics will be a first step achieving this goal. fi Drosophila 1State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Numb was originally identi ed and investigated in . Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao The Numb protein has been found to be distributed asym- Tong University, Shanghai, China. 2School of Biomedical Engineering and Med-X metrically during divisions of sensory organ precursors (SOP) Research Institute, Shanghai Jiao Tong University, Shanghai, China. 3Depart- in Drosophila embryos, resulting in different cell fates of ment of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Carlton daughter cells (7, 8). Upon the first division of SOP, Numb and Elm Streets, Buffalo, New York. is selectively distributed into the anterior daughter cell, which Note: Supplementary data for this article are available at Clinical Cancer differentiates into neurons or glia, whereas the posterior Research Online (http://clincancerres.aacrjournals.org/). daughter cell without inheritance of Numb differentiates into Corresponding Authors: Wei-Qiang Gao, Shanghai Jiao Tong University, 160 outer support cells (9–11). The critical importance of Numb Pujian Road, Shanghai, 200127, China. Phone: 86-158-2112-6637; Fax: 86-21- during progenitor cell differentiation and cell fate determina- 6838-3916; E-mail: [email protected]; and Helen He Zhu, tion in hematopoiesis, neurogenesis, cardiac morphogenesis, [email protected] and myogenesis in vertebrates was demonstrated subsequently doi: 10.1158/1078-0432.CCR-17-0913 (12–15). Recently, a growing body of evidence has suggested Ó2017 American Association for Cancer Research. that Numb may act as a tumor suppressor in various tumor www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst July 27, 2017; DOI: 10.1158/1078-0432.CCR-17-0913 Guo et al. Plasmids Translational Relevance The Penco Numb-DsRed-DR retroviral reporter was gener- Castration-resistant prostate cancer (CRPC) remains one of ously donated by Dr. Dean G. Tang (25). The doxycycline the most deadly and incurable cancer types worldwide. Tumor (dox)-inducible lentiviral plasmid Notch-ICD was a gift from cells in samples from CRPC patients display tremendous Rudolf Jaenisch (Addgene plasmid # 61540; ref. 26). We used heterogeneity. Identification of a prostate cancer cell subpop- shRNAtoknockdowntheexpressionofNumbandPTCH1. ulation with greater castration resistance is a key to the devel- The shRNAs were cloned into lentiviral GV298 vector with opment of targeted anti-CRPC treatment strategies. Our pres- IRES-Cherry and puromycin-selective markers (Shanghai ent study reveals that a prostate cancer cell subpopulation GENECHEM Co., Ltd). Detailed information regarding the with low expression of Numb, which is an evolutionarily sequences of shNumb and shPTCH1 is provided in Supple- conserved cell fate determinant, displays greater resistance to mentary Table S4. The fluorescent Numb promoter lentiviral androgen deprivation. Numb is downregulated in prostate reporter was generated by replacing the pCMV gene in the cancer and is negatively associated with the progression of PLVX-AcGFP1-N1 vector (Clontech, Catalog Nos.632154) with prostate cancer. Our in vitro and in vivo studies demonstrate the Numb-2K promoter sequence (from-2913 to þ84). The that Numb plays a suppressive role in prostate cancer and truncated Numb promoter (1K-4K) sequences were amplified castration resistance by inhibiting Notch and Hedgehog sig- andclonedintoapGL3basicluciferasevector(Promega naling. Inhibitors that targeting Notch and Hedgehog signal- #E1751) using standard recombinant DNA methods. The À ing can effectively deplete Numb /low CRPC cells. Collectively, RBP-Jk, GLI and TCF/LEF1 luciferase reporter lentiviruses were these findings shed new light on the development of effective purchased from Shanghai Genomeditech Co., Ltd. Detailed anti-CRPC treatment strategies. information regarding the plasmid components and response elements of the RBPJk, GLI and TCF/LEF1 luciferase reporter is provided in Supplementary Tables S5 and S6. types, including hepatocellular carcinoma, malignant pleural Luciferase reporter assay Numb mesothelioma, and breast cancer (16–18). The downregula- promoter (1K-4K) luciferase reporters were co-trans- tion of Numb is associated with a poor prognosis in hepato- fected into cells with an internal control plasmid expressing fi fl cellular carcinoma (19), salivary gland carcinoma (20), and Renilla luciferase respectively. The re y luciferase and Renilla esophageal squamous cell carcinoma (21). However, the luciferase activities were measured using a luminometer with the expression of Numb is greatly heterogeneous among different Dual-luciferase Reporter Assay System (Promega, E1910). The fi fl fi cellswithinatumormass(22–24). The molecular mechanism re y luciferase activity was quanti ed and normalized to the underlying the downregulation of Numb and the functional Renilla activity. difference between Numb highly expressed and underex- In vivo pressed cancer cells is not well elucidated. xenograft assay m In this study, we aim to elucidate the role of Numb in CRPC The cells were harvested and suspended in 50 L serum-free m development and decipher the transcriptional regulation of the medium and mixed with 50 L Matrigel (BD Biosciences). Then, fl Numb gene in prostate cancer. On the basis a promoter analysis of the mixture was injected subcutaneously into the anks of the Numb gene, we designed a fluorescent protein reporter lenti- 4-week-old BALB/c nude mice (SLAC). The tumor growth was viral system to distinguish between prostate cancer cells with a monitored and recorded weekly after the inoculation. The À high or low Numb expression. We find that Numb /low enriches a volume of the tumor was calculated using the following formula: Â Â 2 fi small subpopulation of smaller and quiescent cells that prefer- 0.5 tumor length tumor width . The mice were sacri ced entially express Notch and Hedgehog downstream and stem-cell–
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 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]
  • 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.
    [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]