Disease relevance of ATP2A3

• The presence of the D17S1828 genetic marker in the cosmid contig enabled us to map the SERCA3 gene (ATP2A3) 11 centimorgans from the top of the short arm p of chromosome 17, in the vicinity of the cystinosis gene locus [1].
• Expression of endomembrane calcium pumps in colon and gastric cancer cells. Induction of SERCA3 expression during differentiation [2].
• We report that SERCA3 expression is significantly reduced or lost in colon carcinomas when compared with normal colonic epithelial cells, which express this enzyme at a high level [2].
• To better characterize the role of SERCA3 in colon carcinogenesis, its expression has been investigated in colonic epithelium, benign lesions, adenomas, and adenocarcinomas [3].
• Inhibition of Sp1-like factor-dependent transcription blocked SERCA3 expression during cell differentiation, and SERCA3 expression was induced by the expression of dominant-negative TCF4 in colon cancer cells [3].

High impact information on ATP2A3

• In conclusion, intracellular calcium homeostasis becomes progressively anomalous during colon carcinogenesis as reflected by deficient SERCA3 expression [3].
• Using HEK293 cells to express human SERCA3a, we were able to measure both ATP-mediated, oxalate-dependent (45)Ca(2+) uptake and Ca(2+)-dependent ATP hydrolysis activities due exclusively to SERCA3 [4].
• Treatment of the tumor cells with butyrate or other established differentiation inducing agents resulted in a marked and specific induction of the expression of SERCA3, whereas the expression of the ubiquitous SERCA2 enzymes did not change significantly or was reduced [2].
• A similar marked increase in SERCA3 expression was found during spontaneous differentiation of post-confluent Caco-2 cells, and this closely correlated with the induction of other known markers of differentiation [2].
• Three novel sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) 3 isoforms. Expression, regulation, and function of the membranes of the SERCA3 family [5].

Biological context of ATP2A3

• By increasing the rate of Ca2+ sequestration, up-regulation of SERCA 3 counteracts the cytosolic increase in Ca2+ concentration [6].
• CONCLUSION/INTERPRETATION: Our result suggests that in white Caucasians, the SERCA3 locus possibly contributes to the genetic susceptibility to Type II diabetes [Diabetologia (1999) 42: 1240-1243] [7].
• METHODS: In this study, the entire coding and the promoter regions of SERCA3 gene were screened by single-strand conformation polymorphism analysis in white Caucasian Type II diabetic patients [7].
• Finally, by fluorescence in situ hybridization and chromosome G-banding analyses, the SERCA3 gene was assigned to human chromosome 17p13.3 [8].
• This is the first indication of an alternative splicing mechanism operating on the SERCA3 gene transcript, which most likely generates SERCA3 isoforms with altered C-termini [8].

Anatomical context of ATP2A3

• Transcription of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase type 3 gene, ATP2A3, is regulated by the calcineurin/NFAT pathway in endothelial cells [6].
• Likewise an antiserum against the rat SERCA3 terminus (C90) binds to SERCA3 expressed in COS cells and to the 97-kDa band in rat platelets, but it does not recognize the human platelet pump [9].
• 3) The co-expression of nearly equal levels of SERCA3 and SERCA2b messengers in human lymphoblastoid Jurkat cells and in proliferating rat mucosal mast cells was also demonstrated by reverse transcriptase polymerase chain reaction [9].
• An organellar-type of Ca2+ pump formerly detected by means of its phosphoprotein intermediate in platelets and in lymphoid cells, and which runs in acid gels at 97 kDa, is now characterized as sarco/endoplasmic reticulum Ca2+ATPase 3 (SERCA3) [9].
• SERCA2a occurs mainly in cardiac and skeletal muscle, whereas SERCA2b occurs ubiquitously and is coexpressed with the related SERCA type 3 (SERCA3) in many tissues [10].

Associations of ATP2A3 with chemical compounds

• We showed that both PMCA1 and SERCA3 isoform protein and mRNA are upregulated two- to three-fold in thapsigargin-treated HLE B-3 cells in a time and dose-dependent manner [11].
• 2) An antiserum directed against an NH2-terminal SERCA3-specific peptide (N89) reacts with SERCA3 expressed in COS cells and with the 97-kDa protein in rat platelets and the corresponding protein in human platelets [9].
• SERCA3 null mutants survive and appear healthy, but endothelium-dependent relaxation of vascular smooth muscle is impaired and Ca(2+) signaling is altered in pancreatic beta cells [12].
• Finally, cells treated with histamine and loaded with fura 2 exhibited an improved capacity in eliminating high cytosolic Ca2+ concentrations, in accordance with an increase in activity of a low-affinity Ca2+-ATPase, like SERCA 3 [6].
• The histamine-induced up-regulation of SERCA 3 was abolished by cyclosporin A and by VIVIT, a peptide that prevents calcineurin and NFAT (nuclear factor of activated T-cells) from interacting, indicating involvement of the calcineurin/NFAT pathway [6].

Physical interactions of ATP2A3

• Studies using photoactivated cross-linker and chimeric Ca-ATPase between SERCA2 and nonmuscle Ca-ATPase (SERCA3) indicated that potential binding residues are located just downstream of the active ATPase site (Asp351) of SERCA2 [13].

Other interactions of ATP2A3

• SERCA3 was not expressed in normal or DD epidermis, but was found in eccrine glands and blood vessels [10].
• Coexpression of the transmembrane sequence of phospholamban (Met-PLN28-52) with SERCA1a, SERCA2a, and SERCA3 inhibited Ca2+ transport by lowering apparent Ca2+ affinity [14].
• As judged by platelet glycoprotein IIIa (GPIIIa) expression, an increase in SERCA3 proteins was observed while that of SERCA2b remained unchanged throughout maturation [15].

Analytical, diagnostic and therapeutic context of ATP2A3

• We report the molecular cloning of two alternatively spliced transcripts from the human SERCA3 gene, ATP2A3, that encode proteins that differ at their carboxy termini by 36 amino acids [16].
• METHODS: Using immunohistochemistry we studied SERCA2a, SERCA2b and SERCA3 expression in nonlesional and lesional skin from seven patients with DD and normal skin from seven control subjects [10].
• Last, by comparative Western blotting of WKY rat and SHR platelet membranes using a recently developed polyclonal anti-SERCA3 antibody, we established that the 97-kDa SERCA and the SERCA3 protein are identical, as immunostaining of the 97-kDa protein revealed a 230 +/- 25% increase in the expression of this protein in SHR versus WKY rat platelets [17].
• Immunofluorescence staining showed that SERCA2b was densely populated on special parts of the nuclear envelope, but SERCA3 only existed in endoplasmic reticulum [18].
• Immunoprecipitation of the SERCA3 variants from platelet membranes using a PL/IM 430-affinity matrix provided evidence that the putative pan-anti-SERCA3 antibody, PL/IM 430, recognizes all SERCA3 protein isoforms [19].

References