title: Novel STIM1-dependent control of Ca2+ clearance regulates NFAT activity during T-cell activation.
abstract: Antigen presentation to the T-cell receptor leads to sustained cytosolic Ca2+elevation, which is critical for T-cell activation. We previously showed that in activated T cells, Ca2+clearance is inhibited by the endoplasmic reticulum Ca2+sensor stromal interacting molecule 1 (STIM1) via association with the plasma membrane Ca2+/ATPase 4 (PMCA4) Ca2+pump. Having further observed that expression of both proteins is increased in activated T cells, the current study focused on mechanisms regulating both up-regulation of STIM1 and PMCA4 and assessing how this up-regulation contributes to control of Ca2+clearance. Using a STIM1 promoter luciferase vector, we found that the zinc finger transcription factors early growth response (EGR) 1 and EGR4, but not EGR2 or EGR3, drive luciferase activity. We further found that neither STIM1 nor PMCA4 is up-regulated when both EGR1 and EGR4 are knocked down using RNA interference. Further, under these conditions, activation-induced Ca2+clearance inhibition was eliminated with little effect on Ca2+entry. Finally, we found that nuclear factor of activated T-cell (NFAT) activity is profoundly attenuated if Ca2+clearance is not inhibited by STIM1. These findings reveal a critical role for STIM1-mediated control of Ca2+clearance in NFAT induction during T-cell activation.-Samakai, E., Hooper, R., Martin, K. A., Shmurak, M., Zhang, Y., Kappes, D. J., Tempera, I., Soboloff, J. Novel STIM1-dependent control of Ca2+clearance regulates NFAT activity during T-cell activation.
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.|Department of Medical Genetics and Molecular Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; and.
authors.forename: Elsie
authors.initials: E
authors.lastname: Samakai
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.|Department of Medical Genetics and Molecular Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; and.
authors.forename: Robert
authors.initials: R
authors.lastname: Hooper
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Kayla A
authors.initials: KA
authors.lastname: Martin
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.|Department of Medical Genetics and Molecular Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; and.
authors.forename: Maya
authors.initials: M
authors.lastname: Shmurak
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
authors.forename: Dietmar J
authors.initials: DJ
authors.lastname: Kappes
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Italo
authors.initials: I
authors.lastname: Tempera
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; soboloff@temple.edu.|Department of Medical Genetics and Molecular Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; and.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Soboloff
mesh_terms: D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D000071737:Stromal Interaction Molecule 1 / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D015220:Calcium Channels; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D002118:Calcium
keywords: EGR1; EGR4; Jurkat; PMCA4; SOCe; calcium