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Renaming the DSCR1/Adapt78 gene family as RCAN: regulators of calcineurin

Kelvin J. A. Davies^*,1, Gennady Ermak^*, Beverley A. Rothermel, Melanie Pritchard, Joseph Heitman, Joohong Ahnn^||, Flavio Henrique-Silva^¶, Dana Crawford^#, Silvia Canaider^**, Pierluigi Strippoli^**, Paolo Carinci^**, Kyung-Tai Min, Deborah S. Fox, Kyle W. Cunningham, Rhonda Bassel-Duby^||||, Eric N. Olson^||||, Zhuohua Zhang^¶¶, R. Sanders Williams^##, Hans-Peter Gerber^***, Mercè Pérez-Riba, Hisao Seo, Xia Cao, Claude B. Klee, Juan Miguel Redondo^||||||, Lois J. Maltais^¶¶¶, Elspeth A. Bruford^###, Sue Povey^###, Jeffery D. Molkentin^****, Frank D. McKeon, Elia J. Duh, Gerald R. Crabtree, Martha S. Cyert^||||||||, Susana de la Luna^¶¶¶¶ and Xavier Estivill^####

^* Ethel Percy Andrus Gerontology Center, and Division of Molecular & Computational Biology, The University of Southern California, Los Angeles, California, USA;

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA;

Centre For Functional Genomics and Human Disease, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia;

Departments of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA;

^|| Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, Korea;

^¶ Department of Genetics and Evolution, Federal University of São Carlos, São Carlos, SP, Brazil;

^# Center for Immunolgy and Microbial Disease, The Albany Medical College, Albany, New York, USA;

^** Department of Histology, Embryology and Applied Biology, University of Bologna, Bologna, Italy;

Neurogenetics Branch, NINDS, National Institutes of Health, Bethesda, Maryland, USA;

Research Institute for Children, and Department of Pediatrics, Louisiana State Health Science Center, Children’s Hospital, New Orleans, Louisiana, USA;

Department of Biology, Johns Hopkins University, Baltimore, Maryland, USA;

^|||| Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA;

^¶¶ Center for Neuroscience and Aging, The Burnham Institute, La Jolla, California, USA;

^## Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA;

^*** Department of Molecular Oncology, Genentech, South San Francisco, California, USA;

Medical and Molecular Genetics Center, IDIBELL, Institut de Recerca Oncològica, Barcelona, Spain;

Department of Endocrinology and Metabolism, Division of Molecular and Cellular Adaptation, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Japan;

Laboratory of Biochemistry, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA;

^|||||| Centro national de Investigationes Cardiovasculares (CNIC), Madrid, Spain;

^¶¶¶ On behalf of the Mouse Genomic Nomenclature Committee, Mouse Genome Informatics (MGI), The Jackson Laboratory, Bar Harbor, Maine, USA;

^### On behalf of the HUGO Gene Nomenclature Committee, The Galton Laboratory, Department of Biology, University College London, London, UK;

^**** Molecular Cardiovascular Biology, Children’s Hospital Medical Center, Cincinnati, Ohio, USA;

Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA;

Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA;

Department of Developmental Biology and Department of Pathology, Stanford University School of Medicine, Stanford, California, USA;

^|||||||| Department of Biological Sciences, Stanford University, Stanford, California, USA;

^¶¶¶¶ ICREA and Gene Function Group, Genes and Disease Program, Center for Genomic Regulation-CRG, Barcelona, Spain; and

^#### Genes and Disease Program, and CeGen Barcelona Genotyping Node, Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain; and Department of Life Sciences, Pompeu Fabra University, Barcelona, Catalonia, Spain

¹Correspondence: Ethel Percy Andrus Gerontology Center, and Division of Molecular & Computational Biology, The University of Southern California, Los Angeles, CA 90089-0191, USA. E-mail: kelvin{at}usc.edu

Key Words: calcipressin • oxidative stress • Down syndrome • Alzheimer disease • MCIP • NFAT

	INTRODUCTION AND SIGNIFICANCE

TOP INTRODUCTION AND SIGNIFICANCE PROPOSAL THE RCAN GENE FAMILY REGULATION OF CALCINEURIN BY... RATIONALE FOR ACCEPTANCE OF... REFERENCES

 
THE SERINE-THREONINE PHOSPHATASE, calcineurin (also known as PP3C, formerly PP2B) plays pivotal roles in a wide series of key biological processes. A new family of regulators of calcineurin (RCANs) has been shown to modulate calcineurin activity under physiological and pathological conditions. Unfortunately, the members of this family have been given some 20 different names over the past 10 years largely because their function as calcineurin regulators was discovered only recently. These diverse names have resulted in great confusion, and still represent a barrier to advancement in the field. In writing this paper, our goals were 1) to bring together all the previous names for members of this RCAN family in one publication, where their identities can be easily compared; 2) to introduce RCAN as a rational, functional name for this gene family; and 3) to propose a coherent nomenclature system for the known RCAN family members, as well as additional ones that may be found in the future.

	PROPOSAL

TOP INTRODUCTION AND SIGNIFICANCE PROPOSAL THE RCAN GENE FAMILY REGULATION OF CALCINEURIN BY... RATIONALE FOR ACCEPTANCE OF... REFERENCES

 
In the interest of advancing work in the field, we propose a unified nomenclature for the family of genes related to the locus initially designated as human DSCR1. The new RCAN nomenclature has been approved by both the HUGO Gene Nomenclature Committee (HGNC) and the Mouse Genomic Nomenclature Committee (MGNC). Homologs, orthologs, and paralogs of this gene, and their protein products, should now be named "regulators of calcineurin" to reflect the ability of most family members to bind and regulate the protein phosphatase enzyme, calcineurin (see Table 1 ). The gene names would be abbreviated as RCAN (Rcan for mouse and rat) and their protein products as RCAN (Rcan for rat and mouse). The original DSCR1 locus on human chromosome 21 would be designated RCAN1. Because all yeast and fungal genes and proteins are named with only three letters and usually a number, regulators of the calcineurin genes would be referred to as RCN1, and the proteins as RCN1, in these species.

The RCAN1 gene consists of seven exons, of which exons 1–4 can be alternatively transcribed or spliced to produce different mRNA isoforms. In the new nomenclature, two identified RCAN1 protein isoforms would be designated RCAN1–1 and RCAN1–4 (see Fig. 1 ). Similarly, the homologous gene locus on human chromosome 6 would be designated RCAN2 (protein isoforms RCAN2–3 and RCAN2–4). The family member on human chromosome 1 would be designated RCAN3. Orthologs from other mammalian species would follow the same numbering scheme based on their relative identity to these three human family members. Structural homologues from species containing only one RCAN family member would be named simply RCAN1, with additional numbered genes added if new loci are identified. When conversing, RCAN may be easily referred to as "R-can" (pronounced "ar-can"). This new naming system provides information regarding an important function of the RCAN genes and proteins, and will make it much easier for outside researchers to access the literature and grasp the potential importance of these highly conserved regulators of calcineurin signaling.

View larger version (16K): [in this window] [in a new window]   Figure 1. The intron/exon structure, transcripts, and protein products of the human RCAN genes. Overall: Note that all structures, exon locations, and protein isoform nomenclature are based on that of the human RCAN1 gene. Genomic distances between exons (i.e., intron sizes) are given in kilobases. RCAN1: Protein isoforms have been named based on the (human) exon location of the translation start site. In the new nomenclature, the various RCAN1 transcripts corresponding to alternative first exons would be designated RCAN1–1, RCAN1–2, etc., as previously proposed (31) . Exons 5, 6, 7 are omitted from the mRNA transcript and protein isoform nomenclature above. This is possible since exons 5, 6, 7 are invariant components of all transcripts so far observed. The transcript encoding RCAN1–1 starts at exon 1 and its expression is stimulated by glucocorticoids. The transcript encoding RCAN1–4 begins at exon 4 and its expression is controlled by oxidative stress, calcium, and calcineurin. One long (RCAN1–1L) and one short (RCAN1–1S) version of the RCAN1–1 protein are generated due to alternative translation initiation sites in the RCAN1–1 transcript. RCAN2: the system of nomenclature used for each mRNA transcript and protein isoform is the same as that proposed for RCAN1. The RCAN2–1,3 and RCAN2–2,3 transcripts both produce the same protein: RCAN2–3. This is because the first initiation codon lies within exon 3. It should be noted that RCAN2–4 (but not RCAN2–1,3 or RCAN2–2,3) is up-regulated by the thyroid hormone. RCAN3: the system of nomenclature used for each mRNA transcript and protein isoform is similar to that proposed for RCAN1. Exon 4b (an exon 4 variant lacking the first 30 bases, leading to a product lacking 10 amino acids) makes it necessary to specify the particular exon included in the RCAN3–4b mRNA isoform. Exon 1 has been redefined as described by Canaider et al. (35) ; the first initiation codon lies within exon 2. The originally published name for RCAN3–2,5 was DSCR1L2-E2E5 (35) , and it has been reported that proteins encoded by these mRNA transcripts interact with cardiac troponin I (TNNI3) (35) and calcineurin (19) .

	THE RCAN GENE FAMILY

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DSCR1/RCAN1 was first identified by the group of Estivill as an expressed sequence on a YAC clone from human chromosome 21 (1) . The YAC clone contained a portion of the chromosome known as the Down syndrome critical region (DSCR) (20 , 21) . Thus, the name "Down syndrome candidate region 1" gene (originally designated "critical region 1" gene), abbreviated as DSCR1, was used for the first previously unidentified gene on this YAC clone. Although we are suggesting a new function-based nomenclature, the relationship of RCAN1/DSCR1 to human Down syndrome still appears strong. Other open reading frames identified from this region became designated as DSCR 2/3/4 (or A/B/C), etc., in the literature until functional data could be linked with their respective activities. Two major protein isoforms of 252 (RCAN1–1) and 197 (RCAN1–4) amino acids are expressed from the RCAN1 gene by alternative promoter usage and first exon choice in humans and the mouse (9 , 22 23 24) . The proximal promoter controlling expression of RCAN1–4 is activated by calcineurin-NFAT signaling (17) in response to different stimuli such as VEGF (25 , 26) and depolarization in neurons (27) , among others. The distal promoter (RCAN1–1) is activated by glucocorticoids (28) and down-regulated by Notch-dependent signaling (29) .

Important insights into the regulation and function of RCAN1/DSCR1/Adapt78 came when the Davies laboratory demonstrated that its expression was transiently induced during cellular adaptation to oxidative stress and calcium stress (4) . They named the gene Adapt78 and went on to show that it is an oxidant stress response gene and a calcium stress response gene that can protect cells from various forms of stress (30 , 31) . A critical breakthrough came when it was demonstrated that the protein could bind to and inhibit the calcium-regulated protein phosphatase calcineurin in yeast (10) , mouse (6) , human (7) , and Cryptococcus neoformans (11) . The yeast homologue was named RCN1 for "regulator of calcineurin 1" (10) . The mouse ortholog was officially designated Dscr1 (22) , but its protein product was published as MCIP1 (6) for "myocyte-enriched calcineurin-interacting protein 1" and later "modulatory calcineurin interacting protein" (32) . The gene from C. neoformans was named CBP1 for calcineurin binding protein 1 (11) . The Drosophila homologue has been published with a variety of names, including NEBULA (nla) for the gene (13) and sarah (sra) for the protein (14) . The Caenorhabditis elegans gene has been named RCN-1 (12) .

The human RCAN2 locus was first published as ZAKI-4 (16) , a gene whose expression was induced in response to thyroid hormone. ZAKI-4 was later designated DSCR1L1 for "DSCR1-like protein 1" (2) . As shown in Fig. 1 , three transcripts (RCAN2–1,3, RCAN2–2,3, and RCAN2–4) and two protein products (RCAN2–3 and RCAN2–4) have been identified (33) . It has also been noted that the RCAN2–4 protein isoform is up-regulated by thyroid hormone (33) via an AKT/PKB-dependent signaling pathway (34) . The RCAN3 gene was identified on the basis of its sequence similarity to RCAN1 and RCAN2, and was named DSCR1L2 (2) . Alternatively spliced RCAN3 isoforms have also been described (2 , 35) . MCIP 1, 2, and 3 standing for "modulatory calcineurin-interacting proteins" were also suggested as a naming scheme for the three mammalian genes (32 , 36) .

This multiplicity of gene and protein names (see Table 1 ) is awkward and highly confusing to those outside the field. The earlier names also provide no functional information and are difficult to apply to genes from diverse species. Based on its ability to inhibit calcineurin, the term "calcipressin" has been suggested (7 , 11) , and has been abbreviated in a variety of ways, including Csp (8) and CALP (9) . More recently, however, it was demonstrated that RCAN1 protein appears to be capable of either inhibiting or facilitating calcineurin signaling depending on the context (36 37 38) . Thus, the name "calcipressin 1" may not accurately reflect the full biological functions of these proteins. Furthermore, the similarity of the name calcipressin to the calcium binding proteins calretinin, calbindin, and calsequestrein implies calcium binding properties, yet there is no evidence that RCANs bind calcium. Therefore, the former designations all seem inadequate when compared with RCAN.

	REGULATION OF CALCINEURIN BY RCANs

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Several laboratories have reported that animal and fungal RCAN1 and RCAN2 can specifically bind to and down-regulate the activity of calcineurin (6 , 7 , 10 , 11 , 33) . Calcineurin is a protein phosphatase enzyme composed of calcineurin A (CnA) and calcineurin B (CnB) subunits. The CnA subunit has a catalytic domain, a CnB binding domain, and a C-terminal regulatory domain. In the absence of calcium, the protein phosphatase calcineurin is inactive because of a C-terminal autoinhibitory domain ("AID") that blocks the active site in the catalytic CnA subunit. The binding of a calcium/calmodulin complex causes a conformational change that removes the AID, thus "activating" the protein phosphatase activity.

It has been shown that RCAN1 and RCAN2 bind calcineurin at or near the catalytic domain of CnA (6 , 7 , 10) . The primary calcineurin binding portion of the RCAN1 protein is encoded by exon 7 (7 , 39) , which is common to all RCAN1 isoforms. This region includes two RCAN1 sites of interaction with calcineurin. One is a PxIxxT motif that resembles a PxIxIT calcineurin-interacting sequence found in NFAT proteins (40) . The second is an ELHA motif that binds to calcineurin but may need to be in a wider amino acid context, such as the CIC motif, in order to inhibit calcineurin (41) . Two additional sites for calcineurin interaction have been reported. One is specific to the N-terminal region of RCAN1–4 (42) . The other is the highly conserved serine-proline (SP) motif (known also as a FLISPP motif), which is a calcineurin substrate. It has been demonstrated, however, that the SP motif is neither sufficient nor required for the inhibition of calcineurin, although it can act as a competitive inhibitor (9 , 38 , 39 , 41 , 42) . The state of phosphorylation of the RCAN1 SP motif correlates with the protein half-life (9) . RCAN binding to calcineurin does not interfere with binding of either the calcium/calmodulin complex or the regulatory B subunit to the catalytic A subunit of calcineurin. In fact, most data indicate that RCAN1 and RCAN2 bind preferentially to the activated form of calcineurin, suggesting that calcium/calmodulin binding facilitates RCAN binding by removing the AID to expose the catalytic domain.

There are ample data indicating that RCAN1 and RCAN2 can bind calcineurin and that increased RCAN levels can inhibit calcineurin’s protein phosphatase activity. Nevertheless, some of the phenotypes observed in yeast, C. neoformans (43) , and mouse mutants lacking RCAN1 or RCAN2 are similar to those observed in mutants lacking calcineurin (18 , 36) . This suggests that RCANs may also be required for proper calcineurin signaling. There is genetic evidence from yeast indicating that phosphorylation of the conserved serine 108 of RCAN-1–4 by GSK-3 may release the inhibitory activity of RCAN and somehow facilitate calcineurin signaling (37) . Similar results have been reported in fungi (43) and mammals (44) . Although the exact mechanism of this process is not known, it has been suggested that GSK-3-phosphorylated RCAN may act on calcineurin in a manner similar to the chaperoning properties of phosphorylated inhibitor-2, relative to the protein phosphatase PP1 (37) . In the case of mammalian RCAN1, the switch seems to depend on 14–3-3 binding (44) . RCAN3 (formerly DSCR1L2) has been shown to bind cardiac troponin I (TNNI3) (35) , and very recently evidence was presented that it also binds calcineurin and inhibits NFAT-dependent gene expression (19) .

	RATIONALE FOR ACCEPTANCE OF A COMMON NAME

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Laboratories around the globe are now studying RCAN genes and their protein products. RCAN1 has been shown to inhibit cardiac hypertrophy (45) , to attenuate angiogenesis and cancer (26) , and to be associated with Down syndrome and Alzheimer disease (5 , 7 , 24 , 46 47 48 49 50) . RCAN1-dependent inhibition of calcineurin and induction of GSK-3ß expression may play important roles in the tau hyperphosphorylation seen in tauopathies such as Alzheimer disease (5 , 24 , 46 , 48) . Key roles for RCAN1 in human physiology and pathology are rapidly emerging (15) . As with many newly discovered genes and proteins, initial confusion over nomenclature often hinders or obscures progress. In this case, the term DSCR1 for Down syndrome candidate or critical region 1 is misleading, because the gene is not technically inside the DSCR as initially defined. Furthermore, since calcineurin activity is fundamental to so many biological processes, it is likely that RCAN1 and other members of this family of calcineurin regulators will have important functions well beyond those related directly to Down syndrome. Fully aware that these proteins may have additional properties, we propose that the DSCR1 gene be renamed to reflect its influence on calcineurin signaling.

We have suggested adopting "regulators of calcineurin" for this family of proteins based on the original name given in yeast because it is straightforward and recognizes the concept that calcineurin activity can either increase or decrease depending primarily on the level of RCAN1 induction. The abbreviations RCAN1, RCAN2, and RCAN3 will be used rather than Rcn1 to avoid confusion with the unrelated rcn1 gene from Arabidopisis (51) and favoring any existing name. To implement this change, we recommend that publications initially include the RCAN and DSCR designations as well as the name previously used by the investigator. We hope that all researchers in this exciting and important field will join with us in embracing this new nomenclature.

Received for publication April 5, 2007. Accepted for publication April 12, 2007.

	REFERENCES

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