title: Inhibition of cytoplasmic p53 differentially modulates Ca(2+) signaling and cellular viability in young and aged striata.
abstract: The p53 protein, a transcription factor with many gene targets, can also trigger apoptosis in the cytoplasm. The disruption of cell homeostasis, such as Ca(2+) signaling and mitochondrial respiration, contributes to the loss of viability and ultimately leads to cell death. However, the link between Ca(2+) signaling and p53 signaling remains unclear. During aging, there are alterations in cell physiology that are commonly associated with a reduced adaptive stress response, thus increasing cell vulnerability. In this work, we examined the effects of a cytoplasmic p53 inhibitor (pifithrin μ) in the striatum of young and aged rats by evaluating Ca(2+) signaling, mitochondrial respiration, apoptotic protein expression, and tissue viability. Our results showed that pifithrin μ differentially modulated cytoplasmic and mitochondrial Ca(2+) in young and aged rats. Cytoplasmic p53 inhibition appeared to reduce the mitochondrial respiration rate in both groups. In addition, p53 phosphorylation and Bax protein levels were elevated upon cytoplasmic p53 inhibition and could contribute to the reduction of tissue viability. Following glutamate challenge, pifithrin μ improved cell viability in aged tissue, reduced reactive oxygen species (ROS) generation, and reduced mitochondrial membrane potential (ΔΨm). Taken together, these results indicate that cytoplasmic p53 may have a special role in cell viability by influencing cellular Ca(2+) homeostasis and respiration and may produce differential effects in the striatum of young and aged rats.
authors.affiliation: Department of Pharmacology, Federal University of São Paulo, São Paulo, SP 04044-020, Brazil. Electronic address: rodrigo_ureshino@yahoo.com.br.
authors.forename: Rodrigo Portes
authors.initials: RP
authors.lastname: Ureshino
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Yi-Te
authors.initials: YT
authors.lastname: Hsu
authors.affiliation: Department of Pharmacology, Federal University of São Paulo, São Paulo, SP 04044-020, Brazil.
authors.forename: Lúcia Garcez
authors.initials: LG
authors.lastname: do Carmo
authors.affiliation: Human and Natural Sciences Center, Federal University of ABC, Santo André, SP 09210-170, Brazil.
authors.forename: César Henrique
authors.initials: CH
authors.lastname: Yokomizo
authors.affiliation: Human and Natural Sciences Center, Federal University of ABC, Santo André, SP 09210-170, Brazil.
authors.forename: Iseli Lourenço
authors.initials: IL
authors.lastname: Nantes
authors.affiliation: Department of Pharmacology, Federal University of São Paulo, São Paulo, SP 04044-020, Brazil.
authors.forename: Soraya Soubhi
authors.initials: SS
authors.lastname: Smaili
mesh_terms: D000367:Age Factors; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D020013:Calcium Signaling / Q000187:drug effects* / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects* / Q000528:radiation effects; D003593:Cytoplasm / Q000378:metabolism*; D018698:Glutamic Acid / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D006706:Homeostasis; D066298:In Vitro Techniques; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014466:Ultraviolet Rays; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C545747:2-phenylacetylenesulfonamide; C494828:Bax protein, rat; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D018698:Glutamic Acid; D005978:Glutathione
keywords: Aging; Calcium; Glutamate; Oxygen consumption; Striatum; p53