title: Ca2+-activated nucleotidase 1, a novel target gene for the transcriptional repressor DREAM (downstream regulatory element antagonist modulator), is involved in protein folding and degradation.
abstract: DREAM is a Ca(2+)-dependent transcriptional repressor highly expressed in neuronal cells. A number of genes have already been identified as the target of its regulation. Targeted analysis performed on cerebella from transgenic mice expressing a dominant active DREAM mutant (daDREAM) showed a drastic reduction of the amount of transcript of Ca(2+)-activated nucleotidase 1 (CANT1), an endoplasmic reticulum (ER)-Golgi resident Ca(2+)-dependent nucleoside diphosphatase that has been suggested to have a role in glucosylation reactions related to the quality control of proteins in the ER and the Golgi apparatus. CANT1 down-regulation was also found in neuroblastoma SH-SY5Y cells stably overexpressing wild type (wt) DREAM or daDREAM, thus providing a simple cell model to investigate the protein maturation pathway. Pulse-chase experiments demonstrated that the down-regulation of CANT1 is associated with reduced protein secretion and increased degradation rates. Importantly, overexpression of wtDREAM or daDREAM augmented the expression of the EDEM1 gene, which encodes a key component of the ER-associated degradation pathway, suggesting an alternative pathway to enhanced protein degradation. Restoring CANT1 levels in neuroblastoma clones recovered the phenotype, thus confirming a key role of CANT1, and of the regulation of its gene by DREAM, in the control of protein synthesis and degradation.
authors.affiliation: Department of Comparative Biomedicine and Food Science, University of Padua, Padua, Italy.
authors.forename: Tito
authors.initials: T
authors.lastname: Calì
authors.forename: Laura
authors.initials: L
authors.lastname: Fedrizzi
authors.forename: Denis
authors.initials: D
authors.lastname: Ottolini
authors.forename: Rosa
authors.initials: R
authors.lastname: Gomez-Villafuertes
authors.forename: Britt
authors.initials: B
authors.lastname: Mellström
authors.forename: Jose R
authors.initials: JR
authors.lastname: Naranjo
authors.forename: Ernesto
authors.initials: E
authors.lastname: Carafoli
authors.forename: Marisa
authors.initials: M
authors.lastname: Brini
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D017931:DNA Primers; D007150:Immunohistochemistry; D051605:Kv Channel-Interacting Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009708:Nucleotidases / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D059748:Proteolysis; D012097:Repressor Proteins / Q000378:metabolism*
chemical_list: C496756:Csen protein, mouse; D017931:DNA Primers; D051605:Kv Channel-Interacting Proteins; D012097:Repressor Proteins; D009708:Nucleotidases; C030287:nucleotidase; D002118:Calcium