The International Journal of Biochemistry & Cell Biology
ReviewTranscriptional control of the calreticulin gene in health and disease
Introduction
Calreticulin is a multifunctional Ca2+ buffering chaperone in the endoplasmic reticulum (ER) (Table 1). As a molecular chaperone, calreticulin binds to the newly synthesized (glyco)proteins, preventing their aggregation and assisting in their correct folding (Hebert and Molinari, 2007, Michalak et al., 2002, Williams, 2006). Together with calnexin and ERp57 the protein forms a folding cycle to control protein folding (Hebert and Molinari, 2007, Michalak et al., 2002). As a modulator of Ca2+ homeostasis, calreticulin binds large quantities of Ca2+ and consequently directly impacts on Ca2+ capacity of the ER (Michalak, 1995). This has important functional implications since Ca2+ is critical for many ER functions including protein folding and posttranslational modification, activation of store-operated Ca2+ influx, apoptosis, lipid and steroid synthesis, to name a few (Groenendyk and Michalak, 2005). Increased expression of calreticulin results in an elevated Ca2+ level in the ER (Bastianutto et al., 1995, Mery et al., 1996). In turn, calreticulin-deficient cells have significantly reduced Ca2+ storage capacity in the ER, which implies the importance of calreticulin in ER Ca2+ storage and buffering (Nakamura et al., 2001b).
Calreticulin is differentially expressed under variety of physiological and pathological conditions (Table 1, Table 2). For example, reduced levels of calreticulin are found in differentiated tissues such as heart and the brain (Abe et al., 1992, Guo et al., 2001, Imanaka-Yoshida et al., 1996, Langdown et al., 2003, Mesaeli et al., 1999a). In contrast calreticulin is up-regulated in highly differentiated tissues or upon induction of ER stress (Luczynski et al., 2007, Waser et al., 1997, Zhang et al., 2007, Zhu and Wang, 1999). Considering a differential expression of calreticulin in many tissues and cell types it is not surprising that the calreticulin gene is under a tight control of several specific transcription factors. It is, therefore, of a great interest to understand the molecular mechanisms responsible for the regulation of calreticulin expression at transcriptional level. In this review we focused on transcriptional regulation of the calreticulin-1 gene (referred to throughout the manuscript as the calreticulin gene) with a major emphasis on its relevance to health and disease.
Section snippets
The calreticulin gene and promoter
Calreticulin is a highly conserved protein found across a diverse species except for yeast and prokaryotes. To date, two calreticulin genes, named calreticulin-1 and calreticulin-2, have been identified in human, pig, rat and mouse and these genes share approximately 50% identity (Persson et al., 2002). The function of calreticulin-2 and regulation of the calreticulin-2 promoter remain to be elucidated. The product of the calreticulin-2 gene has only been detected in testis suggesting that the
Transcriptional regulation of the calreticulin gene in the heart
Cardiac development is a well controlled molecular and morphogenetic event and even small perturbation of this process can have devastating consequences in the form of congenital heart disease. At the molecular level there are a series of transcription factors involved in the regulation of expression of cardiac specific genes. The calreticulin promoter contains several regulatory sites for muscle specific transcription factors including GATA, Nkx2.5, MEF2C and MyoD (Fig. 1) suggesting that the
Calreticulin in the brain and neurodegenerative diseases
Proteomic analysis identified expression of calreticulin in the rat brain (Decca et al., 2006). In situ hybridization of adult mice brain shows a broad and heterogeneous expression of calreticulin mRNA in the discrete neurons throughout the entire brain, including cerebrum, mesencephalon and cerebellum (Abe et al., 1992). Interestingly, calreticulin is more abundant in the mouse embryonic brain than in adult (Zhang et al., 2007). The protein may be essential during early stages of brain
Calreticulin in the liver
Calreticulin is expressed in a very high level in the liver of many species (Fairburn et al., 2006, Khanna et al., 1987, Milner et al., 1991). Interestingly, mice fed with energy restricted diet show significantly reduced expression of ER chaperone proteins including calreticulin in the liver (Dhahbi et al., 1997) suggesting that calreticulin might be involved in the regulation of energy metabolism in the liver. Lipid metabolism is regulated by several transcription factor families, including
Calreticulin in adipose tissue
Adipose tissue, a loose connective tissue composed of adipocytes, is a major energy reserve for the triglyceride storage and also involved in the regulation of energy homeostasis (Rosen and Spiegelman, 2006). Adipogenesis is a process in which non-adipocyte cells accumulate lipid and develop into mature adipocytes. Ca2+ plays important role in the regulation of adipogenesis and obesity (Draznin et al., 1988, Ntambi and Takova, 1996, Shi et al., 2000, Szabo et al., 2008). DNA microarray analysis
Calreticulin and cancer
The role of calreticulin in cancer has now been established for several years (Bini et al., 1997, Pike et al., 1998). The protein is highly expressed in the human breast carcinoma and hepatoma cells (Bini et al., 1997, Yu et al., 2000). In human prostate cancer cells, androgen induction increases the mRNA level of calreticulin indicating that the protein might be an androgen-response gene in prostate cancer (Zhu and Wang, 1999). Furthermore, calreticulin has also been identified as a marker for
Calreticulin and autoimmune diseases
Calreticulin has been identified as an antigen in sera from patients suffering from several autoimmune diseases including systemic lupus erythematosus (SLE) (Kishore et al., 1997, van den Berg et al., 1998), celiac disease (Alaedini and Green, 2008), rheumatic disease (Jorgensen et al., 2005) and various parasitic diseases (Nakhasi et al., 1998), which implies a pathological role of calreticulin in autoimmune diseases. Parasite calreticulin also impacts on parasite infectivity by modulating the
Calreticulin and wound healing
Calreticulin-deficient embryonic stem cell-derived neural cells have been shown slower cell migration using the wound healing assay (Rauch et al., 2000). Recent studies indicate that calreticulin induced cell migration, cell proliferation and wound closure in human keratinocytes and fibroblasts (Gold et al., 2006). In mouse and porcine models of skin injury, calreticulin enhances wound healing through a dose-dependent increase in epithelial migration and the formation of granulation tissue (
Crosstalk between calreticulin and transcription factors
Calreticulin is an important modulator for Ca2+ homeostasis in many cells. Since Ca2+ signaling from the ER impacts on many cellular functions through Ca2+-dependent signaling pathway such as Ca2+/calmodulin/calcineurin/NF-AT and Ca2+/Ras/MAPK pathway (Michalak et al., 2002), it is conceivable that calreticulin may modulate the transcriptional regulation. Calreticulin inhibits the steroid-dependent gene expression by direct interaction with the DNA-binding domain of steroid receptors (Burns et
Conclusion
As a multifunctional and multi-compartmental protein, calreticulin is involved in many biological functions. Studies on calreticulin-deficient mice reveal that the protein is important for heart development and embryogenesis. Several transcription factors control expression of calreticulin in many different tissues. Extensive studies on the function of calreticulin reveal that a crosstalk exists between the protein and transcription factors. Not only transcription factors regulate calreticulin
Acknowledgments
We are grateful to Dr. Opas (University of Toronto) for helpful comments and suggestions. Work in our laboratory is supported by grants from CHIR (MOP-53050, MOP-15415, MOP-15291), AHFMR and HSFA. Y.Q. is supported by the Faculty of Medicine and Dentistry 75th Anniversary Scholarship.
References (93)
- et al.
Localization of gene expression of calreticulin in the brain of adult mouse
Brain Res
(1992) - et al.
Dietary energy tissue-specifically regulates endoplasmic reticulum chaperone gene expression in the liver of mice
J Nutr
(1997) - et al.
Calreticulin is released from activated neutrophils and binds to C1q and mannan-binding protein
Clin Immunol Immunopathol
(1994) - et al.
In cerebrospinal fluid ER chaperones ERp57 and calreticulin bind beta-amyloid
Biochem Biophys Res Commun
(2005) - et al.
Calreticulin affects beta-catenin-associated pathways
J Biol Chem
(2001) - et al.
Analysis of purified gp96 preparations from rat and mouse livers using 2-D gel electrophoresis and tandem mass spectrometry
Biochimie
(2006) - et al.
Role of calreticulin from parasites in its interaction with vertebrate hosts
Mol Immunol
(2004) - et al.
Overview of the role for calreticulin in the enhancement of wound healing through multiple biological effects
J Investig Dermatol Symp Proc
(2006) - et al.
COUP-TF1 antagonizes Nkx2.5-mediated activation of the calreticulin gene during cardiac development
J Biol Chem
(2001) - et al.
Cardiac-specific expression of calcineurin reverses embryonic lethality in calreticulin-deficient mouse
J Biol Chem
(2002)
Analysis of gene expression profile during 3T3-L1 preadipocyte differentiation
Gene
Arrhythmia induced by spatiotemporal overexpression of calreticulin in the heart
Mol Genet Metab
Alterations of expression and distribution of the Ca2+-storing proteins in endo/sarcoplasmic reticulum during differentiation of rat cardiomyocytes
J Mol Cell Cardiol
The 5′-flanking region of the human calreticulin gene shares homology with the human GRP78, GRP94, and protein disulfide isomerase promoters
J Biol Chem
Purification of calreticulin-like protein(s) from spinach leaves
Biochem Biophys Res Commun
Overexpression of calreticulin increases intracellular Ca2+ storage and decreases store-operated Ca2+ influx
J Biol Chem
Endoplasmic reticulum form of calreticulin modulates glucocorticoid-sensitive gene expression
J Biol Chem
Ca2+ signaling and calcium binding chaperones of the endoplasmic reticulum
Cell Calcium
Calreticulin, and not calsequestrin, is the major calcium binding protein of smooth muscle sarcoplasmic reticulum and liver endoplasmic reticulum
J Biol Chem
Congenital heart block: development of late-onset cardiomyopathy, a previously underappreciated sequela
J Am Coll Cardiol
Implications of calreticulin function in parasite biology
Parasitol Today
Calreticulin enahnces procine wound repair by diverse biological effects
Am J Pathol
Role of Ca2+ in the early stages of murine adipocyte differentiation as evidenced by calcium mobilizing agents
Differentiation
Identification of a novel calreticulin isoform (Crt2) in human and mouse
Gene
Calreticulin and calreticulin fragments are endothelial cell inhibitors that suppress tumor growth
Blood
Misfolded proteins, endoplasmic reticulum stress and neurodegeneration
Curr Opin Cell Biol
Heart, brain, and body wall defects in mice lacking calreticulin
Exp Cell Res
Calreticulin modulates the in vitro DNA binding but not the in vivo transcriptional activation by peroxisome proliferator-activated receptor/retinoid X receptor heterodimers
Mol Cell Endocrinol
Differential expression and activity of matrix metalloproteinase-2 and -9 in the calreticulin deficient cells
Matrix Biol
Endoplasmic reticulum stress during the embryonic development of the central nervous system in the mouse
Int J Dev Neurosci
Autoantibodies in celiac disease
Autoimmunity
Overexpression of calreticulin increases the Ca2+ capacity of rapidly exchanging Ca2+ stores and reveals aspects of their lumenal microenvironment and function
J Cell Biol
Protein expression profiles in human breast ductal carcinoma and histologically normal tissue
Electrophoresis
Modulation of gene expression by calreticulin binding to the glucocorticoid receptor
Nature
Suppression of lung tumor growth and metastasis in mice by adeno-associated virus-mediated expression of vasostatin
Clin Cancer Res
Identification and characterization of cDNA clones encoding plant calreticulin in barley
Plant Cell
Calreticulin binds hYRNA and the 52-kDa polypeptide component of the Ro/SS-A ribonucleoprotein autoantigen
J Immunol
Functional characterization of Arabidopsis Calreticulin1a: a key alleviator of endoplasmic reticulum stress
Plant Cell Physiol
Protein arginylation in rat brain cytosol: a proteomic analysis
Neurochem Res
Inhibition of nuclear hormone receptor activity by calreticulin
Nature
The tobacco homolog of mammalian calreticulin is present in protein complexes in vivo
Plant Cell
Transcriptional regulation of metabolism
Physiol Rev
Impaired recognition of apoptotic neutrophils by the C1q/calreticulin and CD91 pathway in systemic lupus erythematosus
Arthritis Rheum
Possible role of cytosolic free calcium concentrations in mediating insulin resistance of obesity and hyperinsulinemia
J Clin Invest
Pathophysiological roles of calreticulin in autoimmune disease
Scand J Immunol
Anti-Ro/SSA and La/SSB antibodies
Autoimmunity
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