Disease relevance of ATP2B4

• Characterization of PMCA mRNA isoforms revealed that PMCA1b and PMCA4 mRNA are expressed in MCF-7, MDA-MB-231, SK-BR-3, ZR-75-1 and BT-483 breast cancer cell lines [1].

High impact information on ATP2B4

• Using this approach, we discovered that the plasma membrane calcium ATPase 4 (PMCA4) is required for TNF-induced cell death in L929 cells [2].
• Resistance to tumor necrosis factor-induced cell death mediated by PMCA4 deficiency [2].
• Under basal conditions, PMCA4-deficient (PMCA(mut)) cells have a normal phenotype [2].
• Transgenic rat lines carrying the human PMCA 4 cDNA under control of the ventricle-specific myosin light chain-2 promoter were established, and expression in the myocardium was ascertained at the mRNA, protein, and functional levels [3].
• Analysis of the expression levels of alpha-1 syntrophin protein in the heart, skeletal muscle, brain, uterus, kidney, or liver of PMCA4-/- mice, did not reveal any differences when compared with those found in the same tissues of wild-type mice [4].

Biological context of ATP2B4

• The genes for PMCA isoforms 1 and 4 (ATP2B1 and ATP2B4) have been previously localized to human chromosomes 12q21-->q23 and 1q25-->q32, respectively [5].
• We cloned and sequenced eight cDNA inserts encoding for the PMCA1 and PMCA4 variants from a fetal human heart cDNA library confirming that these are the two main PMCA genes expressed in cardiac muscle [6].
• When the human PMCA4 gene spanning this region of variable exon splicing was sequenced, it confirmed the intron-exon boundaries where alternate splicing occurs to produce PMCA4a and PMCA4b [7].
• As has also been shown for PMCA1a, this insertion produced a shift in the reading frame at the 3'-end of the PMCA4 mRNA that yielded a sequence encoding a Ca(2+)-ATPase lacking a large portion of the C-terminal regulatory domain [7].
• The PDZ protein-binding COOH-terminal tail of PMCA2b was not responsible for its apical membrane localization, as a chimeric pump made of an NH(2)-terminal portion from PMCA4 and a COOH-terminal tail from PMCA2b was targeted to the basolateral domain [8].

Anatomical context of ATP2B4

• PMCA4 was the predominant isoform, and was expressed along the plasma membrane of cells in all layers of CE, except with a notable absence along the basal cell membranes adjacent to the stroma [9].
• In contrast to PMCA4, PMCA1 immunoreactivity (IR) was located on portions of basal cell plasma membranes adjacent to the stroma [9].
• We have found that PMCA1 and PMCA4 genes were expressed in 8-, 12- and 20-week fetal heart and in adult heart [6].
• The 14-3-3epsilon protein immunoprecipitated with PMCA4 (not with PMCA2) when expressed in HeLa cells [10].
• Unexpectedly, the truncated PMCA3 and PMCA4 were as effective as the full-length variants in influencing the homeostasis of Ca2+ in the cytosol and the organelles [11].

Associations of ATP2B4 with chemical compounds

• Vitamin D3 dependent Ca-binding protein 28k (CaBP28k), a factor involved in Ca2+ influx, and plasma membrane Ca ATPases (PMCA), a factor involved in Ca2+ efflux, were studied in hypertensive 16-week-old SHR and normotensive Wistar-Kyoto rats (WKY). mRNA levels for CaBP28k, PMCA 2 and PMCA 4 were not different in the two strains [12].
• Partial sequencing of the cross-linked, radioactive peptides has identified a site of the pump located C terminally to the phosphoenzyme-forming aspartic acid, spanning residues 537-544 of the hPMCA4 isoform of the enzyme [13].
• The PMCA2CI protein was maximally activated by 0.5% ethanol, a concentration 8-10 times lower than that needed to obtain the same effect on the PMCA4 protein or on the pump of erythrocyte membranes, which is a mixture of isoforms 1 and 4 [14].
• Flow cytometry kinetic studies of MXR efflux showed that MXRG cells effluxed 50% of the drug at a faster rate than MXRA and MXRT cells (t50: 15.3 min vs. 27.8 and 44.5 min, respectively) [15].

Regulatory relationships of ATP2B4

• Expression of other isoforms such as PMCA4 may influence mammary gland epithelial cell proliferation and aberrant regulation of PMCA isoform expression may lead or contribute to mammary gland pathophysiology in the form of breast cancers [16].

Other interactions of ATP2B4

• The plasma membrane Ca(2+)-pumping ATPase (Ca(2+)-ATPase) mRNAs are encoded on four different genes designated PMCA1-PMCA4 [7].
• Immunocytochemical experiments demonstrated that CRH-R1, CRH, and PMCA4 were up-regulated in cerebellar cortex of mutant rats [17].
• In addition, PMCA4 expression shows little variation across eight drug-treated cell lines and was found to be superior to GAPDH and HPRT1, commonly used reference genes [18].

Analytical, diagnostic and therapeutic context of ATP2B4

• To explore whether PMCA2 and PMCA4 expression may be deregulated in breast cancer, we compared mRNA expression of these PMCA isoforms in tumorigenic and non-tumorigenic human breast epithelial cell lines using real time RT-PCR [16].

References