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      Overlapping ATP2C1 and ASTE1 Genes in Human Genome: Implications for SPCA1 Expression?

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          The ATP2C1 gene encodes for the secretory pathway calcium (Ca 2+)-ATPase pump (SPCA1), which localizes along the secretory pathway, mainly in the trans-Golgi. The loss of one ATP2C1 allele causes Hailey-Hailey disease in humans but not mice. Examining differences in genomic organization between mouse and human we speculate that the overlap between ATP2C1 and ASTE1 genes only in humans could explain this different response to ATP2C1 dysregulation. We propose that ASTE1, overlapping with ATP2C1 in humans, affects alternative splicing, and potentially protein expression of the latter. If dysregulated, the composition of the SPCA1 isoform pool could diverge from the physiological status, affecting cytosolic Ca 2+-signaling, and in turn perturbing cell division, leading to cell death or to neoplastic transformation.

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          Most cited references 28

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          Store-independent activation of Orai1 by SPCA2 in mammary tumors.

          Ca(2+) is an essential and ubiquitous second messenger. Changes in cytosolic Ca(2+) trigger events critical for tumorigenesis, such as cellular motility, proliferation, and apoptosis. We show that an isoform of Secretory Pathway Ca(2+)-ATPase, SPCA2, is upregulated in breast cancer-derived cells and human breast tumors, and suppression of SPCA2 attenuates basal Ca(2+) levels and tumorigenicity. Contrary to its conventional role in Golgi Ca(2+) sequestration, expression of SPCA2 increased Ca(2+) influx by a mechanism dependent on the store-operated Ca(2+) channel Orai1. Unexpectedly, SPCA2-Orai1 signaling was independent of ER Ca(2+) stores or STIM1 and STIM2 sensors and uncoupled from Ca(2+)-ATPase activity of SPCA2. Binding of the SPCA2 amino terminus to Orai1 enabled access of its carboxyl terminus to Orai1 and activation of Ca(2+) influx. Our findings reveal a signaling pathway in which the Orai1-SPCA2 complex elicits constitutive store-independent Ca(2+) signaling that promotes tumorigenesis. Copyright © 2010 Elsevier Inc. All rights reserved.
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            The medial-Golgi ion pump Pmr1 supplies the yeast secretory pathway with Ca2+ and Mn2+ required for glycosylation, sorting, and endoplasmic reticulum-associated protein degradation.

             G Dürr,  D Wolf,  P Catty (1998)
            The yeast Ca2+ adenosine triphosphatase Pmr1, located in medial-Golgi, has been implicated in intracellular transport of Ca2+ and Mn2+ ions. We show here that addition of Mn2+ greatly alleviates defects of pmr1 mutants in N-linked and O-linked protein glycosylation. In contrast, accurate sorting of carboxypeptidase Y (CpY) to the vacuole requires a sufficient supply of intralumenal Ca2+. Most remarkably, pmr1 mutants are also unable to degrade CpY*, a misfolded soluble endoplasmic reticulum protein, and display phenotypes similar to mutants defective in the stress response to malfolded endoplasmic reticulum proteins. Growth inhibition of pmr1 mutants on Ca2+-deficient media is overcome by expression of other Ca2+ pumps, including a SERCA-type Ca2+ adenosine triphosphatase from rabbit, or by Vps10, a sorting receptor guiding non-native luminal proteins to the vacuole. Our analysis corroborates the dual function of Pmr1 in Ca2+ and Mn2+ transport and establishes a novel role of this secretory pathway pump in endoplasmic reticulum-associated processes.
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              Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease.

               Z. Hu,  T Mauro,  G Bench (2000)
              Hailey-Hailey disease (HHD, MIM 16960) is inherited in an autosomal dominant manner and characterized by persistent blisters and erosions of the skin. Impaired intercellular adhesion and epidermal blistering also occur in individuals with pemphigus (which is due to autoantibodies directed against desmosomal proteins) and in patients with Darier disease (DD, MIM 124200), which is caused by mutations in a gene encoding a sarco/endoplasmic reticulum (ER)-Golgi calcium pump. We report here the identification of mutations in ATP2C1, encoding the human homologue of an ATP-powered pump that sequesters calcium into the Golgi in yeast, in 21 HHD kindreds. Regulation of cytoplasmic calcium is impaired in cultured keratinocytes from HHD patients, and the normal epidermal calcium gradient is attenuated in vivo in HHD patients. Our findings not only provide an understanding of the molecular basis of HHD, but also underscore the importance of calcium control to the functioning of stratified squamous epithelia.

                Author and article information

                Int J Mol Sci
                Int J Mol Sci
                International Journal of Molecular Sciences
                January 2013
                04 January 2013
                : 14
                : 1
                : 674-683
                [1 ]School of Biosciences, University of Exeter, Exeter, England EX4 4QD, UK
                [2 ]Division of Molecular Cell Biology, Institute for Molecular Bioscience, the University of Queensland, 306 Carmody Road, St. Lucia, Brisbane QLD 4072, Australia
                [3 ]Faculty of Health Sciences, The Southbank Institute of Technology, 66 Ernest Street, South Brisbane QLD 4101, Australia; E-Mail: l.malquori@
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: m.micaroni@ ; Tel.: +61-7-3346-2035.
                © 2013 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (



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