title: Repression of transcription of presenilin-1 inhibits γ-secretase independent ER Ca²⁺ leak that is impaired by FAD mutations.
abstract: Genetic deletion or mutations of presenilin genes (PS1/PS2) cause familial Alzheimer's disease and calcium (Ca²⁺) signaling abnormalities. PS1/PS2 act as endoplasmic reticulum (ER) Ca²⁺ leak channels that facilitate passive Ca²⁺ leak across ER membrane. Studies with PS1/PS2 double knockout (PS1/PS2-DKO) mouse embryonic fibroblasts showed that PS1/PS2 were responsible for 80% of passive Ca²⁺ leak from the lumen of endoplasmic reticulum to cytosol. Transient transfection of the wild type PS1 expression construct increased cytoplasmic Ca²⁺ as a result of Ca²⁺ leak across ER membrane whereas the FADPS1 (PS1-M146V) mutation construct alone or in combination with the wild type PS1 expression construct abrogated Ca²⁺ leak in SK-N-SH cells. Inhibition of basal c-jun-NH2-terminal kinase (JNK) activity by JNK inhibitor SP600125 repressed PS1 transcription and PS1 protein expression by augmenting p53 protein level in SK-N-SH cells (Lee and Das 2008). In this report we also showed that repression of PS1 transcription by JNK inhibitor SP600125 inhibited passive Ca²⁺ leak across ER membrane which could be rescued by expressing PS1 wild type and not by expressing FADPS1 (PS1-M146V) under a SP600125 non-responsive promoter. Treatment of SK-N-SH cells with SP600125 also triggered InsP3R-mediated Ca²⁺ release from the ER by addition of 500 nM bradykinin, an agonist of InsP3 receptor (InsP3R1) without changing the expression of InsP3R1. This data confirms that SP600125 increases the Ca²⁺ store in the ER by inhibiting PS1-mediated Ca²⁺ leak across ER membrane. p53, ZNF237 and Chromodomain helicase DNA-binding protein 3 which are repressors of PS1 transcription, also reduced Ca²⁺ leak across ER membrane in SK-N-SH cells but γ-secretase inhibitor or dominant negative γ-secretase-specific PS1 mutant (PS1-D257A) had no significant effect. Therefore, p53, ZNF237, and Chromodomain helicase DNA-binding protein 3 inhibit the function ER Ca²⁺ leak channels to regulate both ER and cytoplasmic Ca²⁺ levels and may potentially control Ca²⁺-signaling function of PS1.
authors.affiliation: Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA. hriday.das@unthsc.edu
authors.forename: Hriday K
authors.initials: HK
authors.lastname: Das
authors.forename: Kissaou
authors.initials: K
authors.lastname: Tchedre
authors.forename: Brett
authors.initials: B
authors.lastname: Mueller
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000873:Anthracenes / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004265:DNA Helicases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008715:Methionine / Q000235:genetics; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D009154:Mutation / Q000235:genetics*; D009447:Neuroblastoma / Q000473:pathology / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D018709:Statistics, Nonparametric; D019284:Thapsigargin / Q000494:pharmacology; D014162:Transfection; D014633:Valine / Q000235:genetics
chemical_list: D000873:Anthracenes; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009687:Nuclear Proteins; D010446:Peptide Fragments; D053764:Presenilin-1; C411564:ZMYM5 protein, human; C432165:pyrazolanthrone; D019284:Thapsigargin; D008715:Methionine; D053829:Amyloid Precursor Protein Secretases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D004265:DNA Helicases; C115322:CHD3 protein, human; D014633:Valine; D002118:Calcium