DOCSLIB.ORG

GSK-3 Kinases Enhance Calcineurin Signaling by Phosphorylation of Rcns

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
GSK-3 Kinases Enhance Calcineurin Signaling by Phosphorylation of Rcns Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press GSK-3 kinases enhance calcineurin signaling by phosphorylation of RCNs Zoe Hilioti,1 Deirdre A. Gallagher,1 Shalini T. Low-Nam,1 Priya Ramaswamy,1 Pawel Gajer,1 Tami J. Kingsbury,1 Christine J. Birchwood,1 Andre Levchenko,2 andKyle W. Cunningham 1,3 1Department of Biology and 2Whitaker Institute for Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland 21218, USA The conservedRCN family of proteins can bindanddirectlyregulate calcin eurin, a Ca2+-activatedprotein phosphatase involvedin immunity, heart growth, muscle development,learning, andother processes. Whereas high levels of RCNs can inhibit calcineurin signaling in fungal andanimal cells, RCNs can also stimulate calcineurin signaling when expressedat endogenouslevels. Here we show t hat the stimulatory effect of yeast Rcn1 involves phosphorylation of a conservedserine residueby Mck1, a mem ber of the GSK-3 family of protein kinases. Mutations at the GSK-3 consensus site of Rcn1 andhuman DS CR1/MCIP1 abolish the stimulatory effects on calcineurin signaling. RCNs may therefore oscillate between stimulatory andinhibitory forms in vivo in a manner similar to the Inhibitor-2 regulators of type 1 protein phosphatase. Computational modeling indicates a biphasic response of calcineurin to increasing RCN concentration such that protein phosphatase activity is stimulatedby low concentrations of phospho-RCN andinhibitedby high concentrations of phospho- or dephospho-RCN. This prediction was verifiedexperimentally in yeast cells expressing Rcn1 or DSCR1/MCIP1 at different concentrations. Through the phosphorylation of RCNs, GSK-3 kinases can potentially contribute to a positive feedback loop involving calcineurin-dependent up-regulation of RCN expression. Such feedback may help explain the large induction of DSCR1/MCIP1 observedin brain of Down syndrome individuals. [Keywords: Calcineurin; calcium signaling; Rcn1p; DSCR1; MCIP; GSK-3] Supplemental material is available at http://www.genesdev.org. Received October 7, 2003; revised version accepted November 18, 2003. The serine/threonine protein phosphatase calcineurin calcineurin control. A better understanding of calcineu- becomes highly stimulated in response to Ca2+ signals rin regulation in vivo may facilitate these efforts. through the direct binding of Ca2+ and calmodulin (Klee Major substrates of calcineurin in vertebrates include et al. 1998; Rusnak and Mertz 2000). The enzyme and its the NFAT family of transcription factors (Crabtree and modes of regulation appear to be broadly conserved Olson 2002). During the activation of T-lymphocytes, for among all animals and fungi as well as many protozoans example, calcineurin dephosphorylates NFATs in the cy- (Hilioti and Cunningham 2003a). Animal and fungal cal- toplasm and promotes their import into the nucleus, cineurins are sensitive to cyclosporin A and FK506, where they induce the transcription of many genes in- which bind directly in association with the receptor pro- volved in lymphocyte activation and proliferation. Phos- teins cyclophilin and FKBP-12. These compounds are phorylation of NFATs by GSK-3 protein kinases de- used routinely in humans as immunosuppressive drugs creases their DNA-binding activity and promotes their to control certain autoimmune disorders and to prevent export from the nucleus, thereby inhibiting spontaneous allograft rejection after transplantation. The chronic side activation (Beals et al. 1997). Similar regulatory circuits effects of these drugs have generated great interest in operate in many other cell types. For example, expres- understanding the roles of calcineurin in different cell sion of hyperactive calcineurin in the developing heart types. The recent realization that, in many pathogenic can induce hypertrophy in transgenic mice, and this ef- fungi, calcineurin promotes resistance to a major class of fect can be mimicked by hyperactive NFAT and amelio- antifungal drugs (Fox and Heitman 2002) has also fueled rated to some degree by hyperactive GSK-3 or the im- interest in developing new strategies for more selective munosuppressive drugs (Molkentin et al. 1998). Specific inhibitors of calcineurin or NFAT in the heart may therefore become useful therapeutics in the treatment of 3Corresponding author. heart failure. E-MAIL [email protected]; FAX (410) 516-5213. Article published online ahead of print. Article and publication date are A family of proteins conserved from yeast to humans, at http://www.genesdev.org/cgi/doi/10.1101/gad.1159204. termed RCNs, was recently identified as endogenous GENES & DEVELOPMENT 18:35–47 © 2004 by ColdSpring Harbor Laboratory Press ISSN 0890-9369/04; www.genesdev.org 35 Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Hilioti et al. regulators of calcineurin (Fuentes et al. 2000; Gorlach et lation of type-1 protein phosphatase (PP1) by inhibitor-2 al. 2000; Kingsbury and Cunningham 2000). In budding (Inh2; Cohen 2002). Our findings demonstrate that cal- yeast, overexpression of either Rcn1 or two of its human cineurin signaling can be significantly modulated by homologs DSCR1/MCIP1 and ZAKI4/MCIP2 strongly GSK-3 through effects on RCNs and provide new oppor- inhibited calcineurin-dependent processes (Kingsbury tunities for the therapeutic control of calcineurin. and Cunningham 2000). Similarly, overexpression of DSCR1/MCIP1 inhibited calcineurin-dependent activa- tion of NFAT and other transcription factors (Fuentes et Results al. 2000; Rothermel et al. 2000). DSCR1/MCIP1 overex- A GSK-3 kinase stimulates calcineurin signaling pression in the developing heart also blocked calcineu- in yeast rin-induced cardiac hypertrophy in mouse (Rothermel et al. 2001; Hill et al. 2002). Finally, overexpression of The Pmc1 and Vcx1 Ca2+ transporters in yeast are nec- RCN-1 in nematodes produced phenotypes consistent essary for growth in high-Ca2+ environments but are dif- with calcineurin inhibition (Lee et al. 2003). RCNs di- ferentially regulated by calcineurin (Cunningham and rectly interact with calcineurin in vivo, and purified re- Fink 1996). Calcineurin directly or indirectly inhibits combinant DSCR1/MCIP1 can bind to the catalytic sub- Vcx1, which causes diminished growth rates in high unit of calcineurin in vitro and potently inhibit the Ca2+ conditions, especially in the absence of Pmc1. Con- protein phosphatase activity of the holoenzyme (Gorlach sequently, calcineurin-deficient mutants can be easily et al. 2000; Kingsbury and Cunningham 2000; Rothermel isolated by selection for Ca2+ resistance in a pmc1 mu- et al. 2000; Vega et al. 2002). tant background. Previously we isolated 28 such variants The hypothesis that RCNs serve purely as inhibitors and determined that half of these carried mutations in of calcineurin is unable to explain several observations the CNB1 gene encoding the B subunit of calcineurin in yeast and mouse. Disruption of the RCN1 gene in (Cunningham and Fink 1994). Of the remaining mu- yeast resulted in significantly lower calcineurin signal- tants, 11 were found to carry recessive alleles of the ing in contrast to the expected increase in calcineurin MCK1 gene (see Materials and Methods). Loss-of-func- signaling (Kingsbury and Cunningham 2000). The stimu- tion mutations in MCK1 were unexpected because this latory effect of endogenous Rcn1 on calcineurin signal- gene encodes a member of the GSK-3 family of serine/ ing was not peculiar to yeast because human DSCR1/ threonine protein kinases (Woodgett 2001), and GSK-3 MCIP1 also stimulated calcineurin signaling when ex- kinases frequently antagonize calcineurin signaling by pressed in rcn1 mutants (Kingsbury and Cunningham phosphorylating calcineurin targets. Disruption of the 2000). Homozygous disruption of the DSCR1/MCIP1 MCK1 gene increased the Ca2+ tolerance of pmc1 tcn1 gene in mouse resulted in diminished calcineurin func- double mutants but not of pmc1 tcn1 vcx1 triple mu- tion in the heart under normal circumstances and in re- tants (Fig. 1), indicating that Mck1 does not antagonize sponse to certain stresses such as pressure overload (Vega calcineurin but cooperates with calcineurin to inhibit et al. 2003). Thus, RCNs seem to stimulate calcineurin Vcx1. Complete inhibition of calcineurin with FK506 signaling when expressed at their physiological levels. produced a similar degree of Ca2+ tolerance as the loss of Expression of RCN1 and DSCR1/MCIP1 genes is Mck1 and FK506 did not further increase the Ca2+ toler- strongly up-regulated in response to calcineurin signal- ance of the Mck1-deficient strain (Fig. 1). The Mck1 pro- ing (Fuentes et al. 2000; Kingsbury and Cunningham tein kinase and calcineurin protein phosphatase there- 2000; Rothermel et al. 2000), and therefore the accumu- fore appear to function cooperatively in a pathway that lation of RCNs may generate either positive or negative regulates Vcx1 function. feedback depending on the level of expression. Because Independent of its effects on Vcx1, calcineurin dephos- the DSCR1/MCIP1 gene is overexpressed in the brain of phorylates and activates the Tcn1/Crz1 transcription trisomy 21 individuals and is located within the Down factor, which induces expression of target genes such as syndrome critical region of Chromosome 21 (Fuentes et PMC1, RCN1, and FKS2 (Matheos et al. 1997; Statho- al. 2000), a clearer understanding of the stimulatory and poulos and Cyert 1997; Kingsbury and Cunningham inhibitory
Load more

Recommended publications
  • Cooperation to Amplify Gene-Dosage-Imbalance Effects
    Update TRENDS in Molecular Medicine Vol.12 No.10 Research Focus Cooperation to amplify gene-dosage-imbalance effects Susana de la Luna1 and Xavier Estivill2 1 ICREA and Gene Function Group, Genes and Disease Program, Center for Genomic Regulation-CRG, 08003-Barcelona, Spain 2 Genetic Causes of Disease Group, Genes and Disease Program, Center for Genomic Regulation-CRG and Pompeu Fabra University, Barcelona Biomedical Research Park, 08003-Barcelona, Spain Trisomy 21, also known as Down syndrome (DS), is a From gene-dosage imbalance to pathology complex developmental disorder that affects many ThepresenceofanextracopyofHSA21 genes predicts an organs, including the brain, heart, skeleton and increased expression of 1.5-fold at the RNA level for immune system. A working hypothesis for understand- those genes in trisomy. Experiments in which this effect ing the consequences of trisomy 21 is that the over- has been evaluated indicate that this is indeed the case expression of certain genes on chromosome 21, alone for most HSA21 genes in DS samples and for their or in cooperation, is responsible for the clinical features orthologs in mouse trisomic models [3].Inthesimplest of DS. There is now compelling evidence that the scenario, the overexpression of one specific gene would protein products of two genes on chromosome 21, lead to the disturbance of a biological process and, as a Down syndrome candidate region 1 (DSCR1)and result, a single gene would be responsible for each patho- dual-specificity tyrosine-(Y)-phosphorylation regulated logical feature of DS. However, it is more probable that kinase 1A (DYRK1A), interact functionally, and that the overexpression of several of the 250 HSA21 genes their increased dosage cooperatively leads to dysregu- would contribute to alter a functional pathway in a lation of the signaling pathways that are controlled by specific cell at a specific time.
    [Show full text]
  • RCAN2 Isoform 2 Recombinant Protein Cat
    RCAN2 Isoform 2 Recombinant Protein Cat. No.: 95-114 RCAN2 Isoform 2 Recombinant Protein Specifications SPECIES: Mouse SOURCE SPECIES: E. coli SEQUENCE: aa 2 - 197 FUSION TAG: Fusion Partner: C-terminal His-tag TESTED APPLICATIONS: ELISA, WB APPLICATIONS: This recombinant protein can be used for WB and ELISA. For research use only. PREDICTED MOLECULAR 26 kDa (Calculated) WEIGHT: Properties PURITY: ~95% PHYSICAL STATE: Liquid 100mM sodium phosphate, 10mM Tris, 500mM NaCl, 25 mM imidazole, 2mM MgCl2, 10% BUFFER: gycerol Store in working aliquots at -70˚C. Avoid freeze/thaw cycles. When working with proteins STORAGE CONDITIONS: care should be taken to keep recombinant protein at a cool and stable temperature. September 29, 2021 1 https://www.prosci-inc.com/rcan2-isoform-2-recombinant-protein-95-114.html Additional Info OFFICIAL SYMBOL: Rcan2 RCAN2 Antibody: Csp2, MCIP2, ZAKI-4, Dscr1l1, Zaki4, Calcipressin-2, Calcineurin inhibitory ALTERNATE NAMES: protein ZAKI-4 ACCESSION NO.: AAH62141 PROTEIN GI NO.: 38328420 GENE ID: 53901 Background and References Regulator of calcineurin 2 (RCAN2), also known as ZAKI4 and DSCR1L1, is expressed as two isoforms differing at their N-terminus. The longer of the two (isoform 1) is expressed exclusively in the brain, while isoform 2 is ubiquitously expressed, with highest expression in brain, heart, and muscle (1,2). Both isoforms bind to the catalytic subunit of calcineurin, a Ca++-dependent protein phosphatase involved in several neuronal functions, though BACKGROUND: their C-terminal region and inhibit calcineurin’s activity (3). Unlike isoform 1 of RCAN2, the expression of the second isoform is not induced by the thyroid hormone T3 (3).
    [Show full text]
  • Regulator of Calcineurin (RCAN): Beyond Down
    Molecules and Cells Minireview Regulator of Calcineurin (RCAN): Beyond Down Syndrome Critical Region Sun-Kyung Lee1,2,* and Joohong Ahnn1,2,* 1Department of Life Science, 2Research Institute for Natural Sciences, College of Natural Sciences, Hanyang University, Seoul 04763, Korea *Correspondence: [email protected] (SKL); [email protected] (JA) https://doi.org/10.14348/molcells.2020.0060 www.molcells.org The regulator of calcineurin (RCAN) was first reported as RCAN3 a novel gene called DSCR1, encoded in a region termed the Down syndrome critical region (DSCR) of human chromosome 21. Genome sequence comparisons across INTRODUCTION species using bioinformatics revealed three members of the RCAN gene family, RCAN1, RCAN2, and RCAN3, present in The regulator of calcineurin (RCAN) was first reported as a most jawed vertebrates, with one member observed in most Down syndrome critical region 1 (DSCR1), which is encoded invertebrates and fungi. RCAN is most highly expressed in in a region that at that time was thought to participate in the brain and striated muscles, but expression has been reported onset of Down syndrome (DS) (Antonarakis, 2017; Fuentes in many other tissues, as well, including the heart and et al., 1995). Soon after, evidence showed that RCAN binds kidneys. Expression levels of RCAN homologs are responsive to and regulates the Ca2+/calmodulin-dependent serine/thre- to external stressors such as reactive oxygen species, Ca2+, onine phosphatase calcineurin, whose substrates include nu- amyloid β, and hormonal changes and upregulated in clear factor of activated T cells (NFAT), the transcription factor pathological conditions, including Alzheimer’s disease, that regulates gene expression in many cell types, including cardiac hypertrophy, diabetes, and degenerative neuropathy.
    [Show full text]
  • The Genetic Architecture of Down Syndrome Phenotypes Revealed by High-Resolution Analysis of Human Segmental Trisomies
    The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies Jan O. Korbela,b,c,1, Tal Tirosh-Wagnerd,1, Alexander Eckehart Urbane,f,1, Xiao-Ning Chend, Maya Kasowskie, Li Daid, Fabian Grubertf, Chandra Erdmang, Michael C. Gaod, Ken Langeh,i, Eric M. Sobelh, Gillian M. Barlowd, Arthur S. Aylsworthj,k, Nancy J. Carpenterl, Robin Dawn Clarkm, Monika Y. Cohenn, Eric Dorano, Tzipora Falik-Zaccaip, Susan O. Lewinq, Ira T. Lotto, Barbara C. McGillivrayr, John B. Moeschlers, Mark J. Pettenatit, Siegfried M. Pueschelu, Kathleen W. Raoj,k,v, Lisa G. Shafferw, Mordechai Shohatx, Alexander J. Van Ripery, Dorothy Warburtonz,aa, Sherman Weissmanf, Mark B. Gersteina, Michael Snydera,e,2, and Julie R. Korenbergd,h,bb,2 Departments of aMolecular Biophysics and Biochemistry, eMolecular, Cellular, and Developmental Biology, and fGenetics, Yale University School of Medicine, New Haven, CT 06520; bEuropean Molecular Biology Laboratory, 69117 Heidelberg, Germany; cEuropean Molecular Biology Laboratory (EMBL) Outstation Hinxton, EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom; dMedical Genetics Institute, Cedars–Sinai Medical Center, Los Angeles, CA 90048; gDepartment of Statistics, Yale University, New Haven, CT 06520; Departments of hHuman Genetics, and iBiomathematics, University of California, Los Angeles, CA 90095; Departments of jPediatrics and kGenetics, University of North Carolina, Chapel Hill, NC 27599; lCenter for Genetic Testing,
    [Show full text]
  • DYRK1A and RCAN1
    BMB reports Mini Review Two key genes closely implicated with the neuropathological characteristics in Down syndrome: DYRK1A and RCAN1 Joongkyu Park#, Yohan Oh# & Kwang Chul Chung* Department of Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea The most common genetic disorder Down syndrome (DS) dis- 21) (2, 3). Other phenotypic features of DS include cognitive plays various developmental defects including mental re- impairment, learning and memory deficit, a high risk of leuke- tardation, learning and memory deficit, the early onset of mia, a decreased risk of solid tumors, congenital heart disease Alzheimer’s disease (AD), congenital heart disease, and cranio- and hypotonia (3-5). Moreover, DS brains show additional facial abnormalities. Those characteristics result from the ex- neuropathological outcomes such as the arrest of neurogenesis tra-genes located in the specific region called ‘Down syn- and synaptogenesis, and neuronal differentiation defects (6, 7). drome critical region (DSCR)’ in human chromosome 21. In They also exhibit a lower brain weight with reduced neuronal this review, we summarized the recent findings of the density, number, and volume regardless of region and age (6, DYRK1A and RCAN1 genes, which are located on DSCR and 8, 9). Although the cause of these CNS hypoplasias in DS pa- thought to be closely associated with the typical features of DS tients remains unclear, several reports using DS brains and cul- patients, and their implication to the pathogenesis of neural tured DS fibroblasts suggest that it may result from enhanced defects in DS. DYRK1A phosphorylates several transcriptional cell death and impaired cell proliferation (6, 7, 10, 11).
    [Show full text]
  • Epigenetic Modulations Induction Using DSCR1 Ectopic Expression in Breast Cancer Cells
    Copyright © 2019 Tech Science Press MCB, vol.16, no.1, pp.41-58, 2019 Epigenetic Modulations Induction Using DSCR1 Ectopic Expression in Breast Cancer Cells Zahra Niki Boroujeni1, Atefeh Shirkavand1 and Seyed Ahmad Aleyasin1, * Abstract: Today, prognosis, diagnosis and treatment of cancers are progressing with non-invasive methods, including investigation and modification of the DNA methylation profile in cancer cells. One of the effective factors in regulating gene expression in mammals is DNA methylation. Methylation alterations of genes by external factors can change the expression of genes and inhibit the cancer. In the present study, we investigated the effect of Down syndrome critical region 1 gene (DSCR1) ectopic expression on the methylation status of the BCL-XL, ITGA6, TCF3, RASSF1A, DOK7, VIM and CXCR4 genes in breast cancer cell lines. The effect of DSCR1 ectopic expression on cell viability in MCF7, MDA-MB-468, MDA-MB-231 and MCF10A cell lines was evaluated using MTT assay after the cells treated by lentivirus vectors harboring DSCR1 for 72 hours. Methylation status of BCL-XL, ITGA6, TCF3, RASSF1A, DOK7, VIM and CXCR4 genes in breast cancer cell lines was assessed by Restriction Enzyme PCR (REP) method. Also, methylation changes of these genes in breast cancer cell lines after treatment by lentivirus vectors harboring DSCR1 for 7 days were analyzed by REP method. To confirm the effect of DSCR1 on methylation of genes, Real-time PCR was performed. The MTT assay results indicated that DSCR1 ectopic expression reduced cell viability in all three human breast cancer cell lines. Our results showed that DSCR1 ectopic expression after 6 days reversed the hypomethylation status of the BCL- XL, ITGA6, TCF3, VIM and CXCR4 genes and hypermethylation of RASSF1A and DOK7 genes.
    [Show full text]
  • Human RCAN3 Gene Expression and Cell Growth in Endothelial Cells
    913-918.qxd 19/10/2010 09:34 Ì ™ÂÏ›‰·913 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 26: 913-918, 2010 913 Human RCAN3 gene expression and cell growth in endothelial cells SILVIA CANAIDER1, MARINA VETTRAINO1, LUCY V. NORLING2, ENZO SPISNI3, FEDERICA FACCHIN1, DIANNE COOPER2 and MAURO PERRETTI2 1Department of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, Bologna, Italy; 2William Harvey Research Institute, Queen Mary University of London, Bart's and The London Medical School, Charterhouse Square, London, EC1M 6BQ, UK; 3Department of Experimental Biology, University of Bologna, via Selmi 3, 40126 Bologna, Italy Received May 28, 2010; Accepted July 20, 2010 DOI: 10.3892/ijmm_00000542 Abstract. Regulator of calcineurin 3 (RCAN3) belongs to the recent paper (5) will be used here. The human RCAN3 gene human RCAN gene family, which also includes RCAN1 and (1p36.11) encodes for a 241 amino acid predicted protein RCAN2. All three members interact with and inhibit calci- (27.5 kDa), is expressed in many human tissues (1,5) and is neurin. Based on this effect, several studies have demonstrated the most recent member of the human RCAN gene family, a role for RCAN1 and RCAN2 on inflammation, using human appearing only in vertebrates (6). RCAN-like proteins are umbilical vein endothelial cells (HUVECs) as a model. conserved from yeast to humans and share a highly conserved RCAN1 and 2 are strongly induced by vascular endothelial consensus motif (FLISPP motif) comprising the signature of growth factor (VEGF), inhibit cell proliferation and down- the family (1). RCAN3 has recently been demonstrated to regulate many pro-inflammatory and pro-angiogenic genes.
    [Show full text]
  • Ectopic Expression of DSCR1 in Conjunction with NDV Infection Reduces VEGF and Induces Apoptosis in Lung Cancer A549 Cell Line
    cer Scien an ce C & f o T l h Rad et al., J Cancer Sci Ther 2019, 11:1 a e n r a Journal of r p u DOI: 10.4172/1948-5956.1000574 y o J ISSN: 1948-5956 Cancer Science & Therapy Research Article Open Access Ectopic Expression of DSCR1 in Conjunction with NDV Infection Reduces VEGF and Induces Apoptosis in Lung Cancer A549 Cell Line Hanie Motahary Rad, Zahra Niki Boroujeni and Ahmad Aleyasin* Department of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran Abstract Lung cancer is one the most cause of cancer related deaths in the world. Newcastle Disease Virus (NDV) is an oncolytic and targeted self-amplifying agent that is able to replicates and kills only cancer cells. The strongest limitation of NDV in cancer treatments is due to its angiogenesis effect for tumors formation. The NDV mechanism for angiogenesis has not been described. This study was to evaluate for the first time the anti-angiogenesis effect of DSCR1 lonely and in conjunction with NDV in lung cancer cells. Ectopic expression of DSCR1 was induced by lentiviral transfection to A549 cell line. Transfected A549 was treated with the effective dose of NDV. Total RNA was extracted and cDNA was synthesized to detect DSCR1, VEGF, PCNA, Bax, and Bcl2 genes expressions compare to HPRT expression as a housekeeping gene using SYBR green Real-time PCR assay. Over expression of VEGF was detected in RNA level for the first time in NDV treated cells. Significant fold changes of PCNA, Bax, and Bcl2 showed that NDV used mitochondrial pathway for induction of cell death.
    [Show full text]
  • National Institutes of Health Research Plan on Down Syndrome
    A revised plan was published in 2014; this archived document is provided for reference only. National Institutes of Health Research Plan on Down Syndrome October 2007 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES (HHS) National Institutes of Health (NIH) Plan Developed by the NIH Down Syndrome Working Group A revised plan was published in 2014; this archived document is provided for reference only. A revised plan was published in 2014; this archived document is provided for reference only. TABLE OF CONTENTS EXECUTIVE SUMMARY .......................................................................................................... 1 SELECTED NIH RESEARCH OBJECTIVES ...................................................................................... 1 INTRODUCTION AND BACKGROUND................................................................................. 2 BACKGROUND ON DOWN SYNDROME .......................................................................................... 2 HIGHLIGHTS OF ONGOING RESEARCH ON DOWN SYNDROME AT THE NIH...... 3 NATIONAL CANCER INSTITUTE (NCI).......................................................................................... 3 NATIONAL HEART, LUNG, AND BLOOD INSTITUTE (NHLBI)....................................................... 4 NATIONAL INSTITUTE ON AGING (NIA)....................................................................................... 5 NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES (NIAID) ................................... 6 NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
    [Show full text]
  • Down Syndrome and Vascular Disease: DSCR1 and NFAT Signaling
    7 Down Syndrome and Vascular Disease: DSCR1 and NFAT Signaling Monica Y. Lee and Brian R. Wamhoff University of Virginia, Robert M. Berne Cardiovascular Research Center U.S.A. 1. Introduction Down Syndrome (DS) is one of the most common genetic disorders to date, occurring in 1 out of every 800-1000 live births (Egan et al. 2004; Roizen & Patterson, 2003; Stoll et al. 1990). DS patients often display several developmental and cognitive deficiencies. Common phenotypes of DS patients include congenital heart disease, dysmorphic physical features, and early-onset Alzheimer’s disease (AD). Since the discovery in 1959 that DS occurs from an extra copy of human chromosome 21 (hChr21) (Lejeune J, Gautier & Turpin, 1959), questions arose whether a 1.5-fold increase in a gene or set of genes were responsible for the phenotypes associated with DS. Sequence analysis of hChr21 indentified over 225 genes and/or predicted genes (Hattori et al. 2000). With the recent advances in sequencing, the gene content of hChr21 is now estimated to exceed 300 genes (Roizen & Patterson, 2003). While typically characterized by complete trisomy of hChr21, several DS cases, however, demonstrate that partial trisomy of hChr21 is enough to elicit the phenotypes associated with DS (Stoll et al. 1990), hence arising the concept of a Down Syndrome Critical Region (DSCR). The DSCR theory suggests that enhanced expression of a few genes located in this critical chromosomal region (between markers D21S17 and D21S55 (Delabar et al. 1993; Korenberg et al. 1994)) are responsible for some, if not all, of the features of DS. Olson LE et al show, however, that triplication of this region alone is not enough to fully manifest the phenotypes associated with DS (Olson et al.
    [Show full text]
  • Increased Dosage of DYRK1A and DSCR1 Delays Neuronal Differentiation in Neocortical Progenitor Cells
    Downloaded from genesdev.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Increased dosage of DYRK1A and DSCR1 delays neuronal differentiation in neocortical progenitor cells 1 Nobuhiro Kurabayashi and Kamon Sanada Molecular Genetics Research Laboratory, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan Down’s syndrome (DS), a major genetic cause of mental retardation, arises from triplication of genes on human chromosome 21. Here we show that DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) and DSCR1 (DS critical region 1), two genes lying within human chromosome 21 and encoding for a serine/ threonine kinase and calcineurin regulator, respectively, are expressed in neural progenitors in the mouse developing neocortex. Increasing the dosage of both proteins in neural progenitors leads to a delay in neuronal differentiation, resulting ultimately in alteration of their laminar fate. This defect is mediated by the cooperative actions of DYRK1A and DSCR1 in suppressing the activity of the transcription factor NFATc. In Ts1Cje mice, a DS mouse model, dysregulation of NFATc in conjunction with increased levels of DYRK1A and DSCR1 was observed. Furthermore, counteracting the dysregulated pathway ameliorates the delayed neuronal differentiation observed in Ts1Cje mice. In sum, our findings suggest that dosage of DYRK1A and DSCR1 is critical for proper neurogenesis through NFATc and provide a potential mechanism to explain the neurodevelopmental defects in DS. [Keywords: Down’s syndrome; developing neocortex; neurogenesis; neural progenitor] Supplemental material is available for this article. Received July 15, 2013; revised version accepted November 7, 2013. Down’s syndrome (DS), which occurs in one in 700–800 including neurological phenotypes (McCormick et al.
    [Show full text]
  • A Conserved Family of Calcineurin Regulators
    Downloaded from genesdev.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press A conserved family of calcineurin regulators Tami J. Kingsbury and Kyle W. Cunningham1 Department of Biology, Johns Hopkins University, Baltimore, Maryland 21218 USA The protein phosphatase calcineurin mediates many cellular responses to calcium signals. Using a genetic screen in yeast, we identified a new family of proteins conserved in fungi and animals that inhibit calcineurin function when overexpressed. Overexpression of the yeast protein Rcn1p or the human homologs DSCR1 or ZAKI-4 inhibited two independent functions of calcineurin in yeast: The activation of the transcription factor Tcn1p and the inhibition of the H+/Ca2+ exchanger Vcx1p. Purified recombinant Rcn1p and DSCR1 bound calcineurin in vitro and inhibited its protein phosphatase activity. Signaling via calmodulin, calcineurin, and Tcn1p induced Rcn1p expression, suggesting that Rcn1p operates as an endogenous feedback inhibitor of calcineurin. Surprisingly, rcn1 null mutants exhibited phenotypes similar to those of Rcn1p-overexpressing cells. This effect may be due to lower expression of calcineurin in rcn1 mutants during signaling conditions. Thus, Rcn1p levels may fine-tune calcineurin signaling in yeast. The structural and functional conservation between Rcn1p and DSCR1 suggests that the mammalian Rcn1p-related proteins, termed calcipressins, will modulate calcineurin signaling in humans and potentially contribute to disorders such as Down Syndrome. [Key Words: Calcineurin; calcium signaling; Rcn1p; DSCR1; ZAKI-4] Received February 21, 2000; revised version accepted May 18, 2000. The calcium and calmodulin-activated protein phospha- 1997; Mendizabal et al. 1998; Stathopoulos-Gerontides tase calcineurin regulates a variety of developmental and et al.
    [Show full text]