Abstract
Calreticulin is a ubiquitous Ca2+ binding protein, located in the endoplasmic reticulum lumen, which has been implicated in many diverse functions including: regulation of intracellular Ca2+ homeostasis, chaperone activity, steroid-mediated gene regulation, and cell adhesion. To understand the physiological function of calreticulin we used gene targeting to create a knockout mouse for calreticulin. Mice homozygous for the calreticulin gene disruption developed omphalocele (failure of absorption of the umbilical hernia) and showed a marked decrease in ventricular wall thickness and deep intertrabecular recesses in the ventricular walls. Transgenic mice expressing a green fluorescent protein reporter gene under the control of the calreticulin promoter were used to show that the calreticulin gene is highly activated in the cardiovascular system during the early stages of cardiac development. Calreticulin protein is also highly expressed in the developing heart, but it is only a minor component of the mature heart. Bradykinin-induced Ca2+ release by the InsP3-dependent pathway was inhibited in crt−/− cells, suggesting that calreticulin plays a role in Ca2+ homeostasis. Calreticulin-deficient cells also exhibited impaired nuclear import of nuclear factor of activated T cell (NF-AT3) transcription factor indicating that calreticulin plays a role in cardiac development as a component of the Ca2+/calcineurin/NF-AT/GATA-4 transcription pathway.
References
64
Referenced
424
10.1021/bi980595z
/ Biochemistry / Interaction between a Ca2+binding protein calreticulin and perforin, a component of the T-cell granules by Andrin (1998){'key': '2023072900282534500_B2'}
10.1016/S0021-9258(18)54661-5
/ J Biol Chem / Expression of calreticulin in Escherichia coli and identification of its Ca2+binding domains by Baksh (1991)10.1083/jcb.130.4.847
/ J Cell Biol / Overexpression of calreticulin increases the Ca2+ capacity of rapidly exchanging Ca2+stores and reveals aspects of their lumenal microenvironment and function by Bastianutto (1995)10.1016/0092-8674(94)90214-3
/ Cell / Stabilization of calcium release channel (ryanodine receptor) function by FK506-binding protein by Brillantes (1994)10.1016/S0021-9258(18)41735-8
/ J Biol Chem / Calreticulin in T-lymphocytes. Identification of calreticulin in T-lymphocytes and demonstration that activation of T-cells correlates with increased levels of calreticulin mRNA and protein by Burns (1992)10.1038/367476a0
/ Nature / Modulation of gene expression by calreticulin binding to the glucocorticoid receptor by Burns (1994){'key': '2023072900282534500_B8'}
10.1016/0092-8674(95)90473-5
/ Cell / Calreticulin inhibits repetitive intracellular Ca2+waves by Camacho (1995)10.1073/pnas.92.5.1784
/ Proc Natl Acad Sci USA / Immunophilin FK506 binding protein associated with inositol 1,4,5-trisphosphate receptor modulates calcium flux by Cameron (1995)10.1073/pnas.93.13.6275
/ Proc Natl Acad Sci USA / Disruption of the MARCKS gene prevents cranial neural tube closure and results in anencephaly by Chen (1996)10.1074/jbc.270.39.23132
/ J Biol Chem / Inducible interaction of integrin α2β1with calreticulin by Coppolino (1995)10.1038/386843a0
/ Nature / Calreticulin is essential for integrin-mediated calcium signaling and cell adhesion by Coppolino (1997)10.1146/annurev.physiol.60.1.267
/ Annu Rev Physiol / Role of cardiac neural crest cells in cardiovascular development by Creazzo (1998)10.1038/32419
/ Nature / Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum by de la Pompa (1998)10.1038/367480a0
/ Nature / Inhibition of nuclear hormone receptor activity by calreticulin by Dedhar (1994)10.1007/BF00174084
/ Anat Embryol / The development of the myocardium and endocardium in mouse embryos. Fusion of two heart tubes? by DeRuiter (1992)10.1038/386855a0
/ Nature / Differential activation of transcription factors induced by Ca2+response amplitude and duration by Dolmetsch (1997)10.1084/jem.177.1.1
/ J Exp Med / The calcium binding protein calreticulin is a major constituent of lytic granules in cytolytic T lymphocytes by Dupuis (1993)10.1101/gad.11.23.3128
/ Genes Dev / Mouse mutant embryos overexpressing IGF-II exhibit phenotypic features of the Beckwith-Wiedemann and Simpson-Golabi-Behmel syndromes by Eggenschwiler (1997)10.1016/S1050-1738(97)00010-8
/ Trends Card Med / Regulation of cardiac gene expression by GATA-4/5/6 by Evans (1997)10.1091/mbc.9.6.1513
/ Mol Biol Cell / Delayed activation of the store-operated calcium current induced by calreticulin overexpression in RBL-1 cells by Fasolato (1998)10.1242/dev.124.11.2099
/ Development / Fashioning the vertebrate heart: earliest embryonic decisions by Fishman (1997)10.1016/S0021-9258(20)88216-7
/ J Biol Chem / Molecular cloning of the high affinity calcium binding protein (calreticulin) of skeletal muscle sarcoplasmic reticulum by Fliegel (1989)10.1016/0005-2736(89)90166-1
/ Biochim Biophys Acta / The high affinity calcium binding protein of skeletal muscle sarcoplasmic reticulum by Fliegel (1989)10.1128/MCB.18.5.2901
/ Mol Cell Biol / Distinct functions are implicated for the GATA-4, -5, and -6 transcription factors in the regulation of intestine epithelial cell differentiation by Gao (1998){'key': '2023072900282534500_B27', 'first-page': '3115', 'article-title': 'A hormone-encoding gene identifies a pathway for cardiac but not skeletal muscle gene transcription', 'volume': '14', 'author': 'Grepin', 'year': '1994', 'journal-title': 'Mol Cell Biol'}
/ Mol Cell Biol / A hormone-encoding gene identifies a pathway for cardiac but not skeletal muscle gene transcription by Grepin (1994)10.1016/S0021-9258(19)36529-9
/ J Biol Chem / Bradykinin-induced cytosolic Ca2+ oscillations and inositol tetrakisphosphate-induced Ca2+ influx in voltage-clamped ras-transformed NIH/3T3 fibroblasts by Hashii (1993)10.1016/S0962-8924(97)01032-5
/ Trends Cell Biol / Calnexin, calreticulin and the folding of glycoproteins by Helenius (1997)10.1083/jcb.142.4.963
/ J Cell Biol / Differential modulation of SERCA2 isoforms by calreticulin by John (1998){'key': '2023072900282534500_B31'}
10.1083/jcb.141.4.863
/ J Cell Biol / Nucleocytoplasmic shuttling factor including Ran and CRM1 mediate nuclear export of NFAT in vitro by Kehlenbach (1998)10.1016/S0092-8674(00)81884-X
/ Cell / Calreticulin by Krause (1997)10.1101/gad.11.8.1048
/ Genes Dev / GATA4 transcription factor is required for ventral morphogenesis and heart tube formation by Kuo (1997)10.1038/227680a0
/ Nature / Cleavage of structural proteins during the assembly of the head of bacteriophage T4 by Laemmli (1970)10.1016/S0021-9258(19)61952-6
/ J Biol Chem / Decreasing calreticulin expression lowers the Ca2+response to bradykinin and increases sensitivity to ionomycin in NG-108-15 cells by Liu (1994)10.1074/jbc.271.16.9332
/ J Biol Chem / Overexpression of calreticulin increases intracellular Ca2+-storage and decreases store-dependent Ca2+influx by Mery (1996)10.1042/bj2850681
/ Biochem J / Calreticulin by Michalak (1992)10.1074/jbc.271.46.29436
/ J Biol Chem / Endoplasmic reticulum form of calreticulin modulates glucocorticoid-sensitive gene expression by Michalak (1996)10.1146/annurev.ph.58.030196.002453
/ Annu Rev Physiol / The polyclonal origin of myocyte lineages by Mikawa (1996)10.1016/S0021-9258(20)89624-0
/ J Biol Chem / Calreticulin, and not calsequestrin, is the major calcium binding protein of smooth muscle sarcoplasmic reticulum and liver endoplasmic reticulum by Milner (1991)10.1101/gad.11.8.1061
/ Genes Dev / Requirement of the transcription factor GATA-4 for heart tube formation and ventral morphogenesis by Molkentin (1997)10.1016/S0092-8674(00)81573-1
/ Cell / A calcineurin-dependent transcriptional pathway for cardiac hypertrophy by Molkentin (1998)10.1006/excr.1993.1063
/ Exp Cell Res / An endoplasmic reticulum protein, calreticulin, is transported into the acrosome of rat sperm by Nakamura (1993)10.1074/jbc.270.9.4741
/ J Biol Chem / Calreticulin functions as a molecular chaperone in the biosynthesis of myeloperoxidase by Nauseef (1995)10.1016/S0021-9258(17)42090-4
/ J Biol Chem / A set of endoplasmic reticulum proteins possessing properties of molecular chaperones includes Ca2+-binding proteins and numbers of the thioredoxin superfamily by Nigam (1994)10.1126/science.272.5262.671
/ Science / Molecular pathways controlling heart development by Olson (1996)10.1083/jcb.135.6.1913
/ J Cell Biol / Calreticulin modulates cell adhesiveness via regulation of vinculin expression by Opas (1996)10.1016/S0021-9258(19)43026-3
/ J Biol Chem / Isolation of a high affinity calcium binding protein from sarcoplasmic reticulum by Ostwald (1974)10.1038/32426
/ Nature / The transcription factor NF-ATc is essential for cardiac valve formation by Ranger (1998)10.1146/annurev.immunol.15.1.707
/ Annu Rev Immunol / Transcription factors of the NF-AT family: regulation and function by Rao (1997)10.1161/01.RES.78.3.349
/ Circ Res / Mouse mutants and cardiac development by Rossant (1996)10.1038/35146
/ Nature / Cardiac defects and altered ryanodine receptor function in mice lacking FKBP12 by Shou (1998)10.1073/pnas.91.26.12770
/ Proc Natl Acad Sci USA / Identification of calreticulin as a rubella virus RNA binding protein by Singh (1994){'key': '2023072900282534500_B55', 'first-page': '155', 'article-title': 'Calreticulin: the diverse functional repertoire of a new human autoantigen', 'volume': '1', 'author': 'Sontheimer', 'year': '1993', 'journal-title': 'Immunologist'}
/ Immunologist / Calreticulin: the diverse functional repertoire of a new human autoantigen by Sontheimer (1993)10.1126/science.8073285
/ Science / Redistribution of intracellular Ca2+stores during phagocytosis in human neutrophils by Stendahl (1994)10.1073/pnas.92.4.944
/ Proc Natl Acad Sci USA / MARCKS deficiency in mice leads to abnormal brain development and perinatal death by Stumpo (1995)10.1146/annurev.physiol.60.1.287
/ Annu Rev Physiol / Molecular insights into cardiac development by Sucov (1998)10.1073/pnas.88.6.2065
/ Proc Natl Acad Sci USA / FVB/N: an inbred mouse strain preferable for transgenic analyses by Taketo (1991)10.1002/(SICI)1097-4652(199603)166:3<547::AID-JCP9>3.0.CO;2-P
/ J Cell Physiol / Regulation of calcium storage proteins, calreticulin and calsequestrin, during differentiation of the myogenic cell line L6 by Tharin (1996)10.1073/pnas.87.7.2466
/ Proc Natl Acad Sci USA / Thapsigargin, a tumor promoter, discharges intracellular Ca2+ stores by specific inhibition of the endoplasmic reticulum Ca2+-ATPase by Thastrup (1990)10.1038/383837a0
/ Nature / Rapid shuttling of NF-AT in discrimination of Ca2+signals and immunosuppression by Timmerman (1996)10.1083/jcb.138.3.547
/ J Cell Biol / Regulation of calreticulin gene expression by calcium by Waser (1997)10.1038/387151a0
/ Nature / Altered cell differentiation and proliferation in mice lacking p57KIP2indicates a role in Beckwith-Wiedemann syndrome by Zhang (1997)
Dates
Type | When |
---|---|
Created | 23 years, 1 month ago (July 26, 2002, 12:45 p.m.) |
Deposited | 2 years, 1 month ago (July 28, 2023, 8:29 p.m.) |
Indexed | 3 weeks, 5 days ago (Aug. 6, 2025, 8 a.m.) |
Issued | 26 years, 5 months ago (March 8, 1999) |
Published | 26 years, 5 months ago (March 8, 1999) |
Published Online | 26 years, 5 months ago (March 8, 1999) |
Published Print | 26 years, 5 months ago (March 8, 1999) |
@article{Mesaeli_1999, title={Calreticulin Is Essential for Cardiac Development}, volume={144}, ISSN={1540-8140}, url={http://dx.doi.org/10.1083/jcb.144.5.857}, DOI={10.1083/jcb.144.5.857}, number={5}, journal={The Journal of Cell Biology}, publisher={Rockefeller University Press}, author={Mesaeli, Nasrin and Nakamura, Kimitoshi and Zvaritch, Elena and Dickie, Peter and Dziak, Ewa and Krause, Karl-Heinz and Opas, Michal and MacLennan, David H. and Michalak, Marek}, year={1999}, month=mar, pages={857–868} }