title: Macrophage migration inhibitory factor induces phosphorylation of Mdm2 mediated by phosphatidylinositol 3-kinase/Akt kinase: Role of this pathway in decidual cell survival.
abstract: The phosphatidylinositol 3-kinase (PI3K)/Akt pathway has an anti-apoptotic effect through several downstream targets, which includes activation of the transformed mouse 3T3 cell double-minute 2 (Mdm2) protein, its translocation to the nucleus and degradation of the tumor suppressor p53. We show that Mif, the Macrophage Migration Inhibitory Factor, an important cytokine at the maternal fetal interface in several species, triggers phosphorylation of Mdm2 protein in a PI3K/Akt-dependent manner, thereby preventing apoptosis in cultured mouse decidual cells. Inhibition of Akt and PI3K suppresses the pathway. Mif treatment also changes the nuclear translocation of p53 and interferes with the apoptotic fate of these cells when challenged with reactive oxygen species. In conclusion, an important mechanism has been found underlying decidual cell survival through Akt signaling pathway activated by Mif, suggesting a role for this cytokine in decidual homeostasis and in the integrity of the maternal-fetal barrier that is essential for successful gestation.
authors.affiliation: Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; Department of Stomatology, Dental School, University of São Paulo, São Paulo, Brazil.
authors.forename: Adriana Fraga
authors.initials: AF
authors.lastname: Costa
authors.affiliation: Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Sara Zago
authors.initials: SZ
authors.lastname: Gomes
authors.affiliation: Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Aline R
authors.initials: AR
authors.lastname: Lorenzon-Ojea
authors.affiliation: Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Mariane
authors.initials: M
authors.lastname: Martucci
authors.affiliation: Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Miriam Rubio
authors.initials: MR
authors.lastname: Faria
authors.affiliation: Department of Stomatology, Dental School, University of São Paulo, São Paulo, Brazil.
authors.forename: Décio Dos Santos
authors.initials: Ddos S
authors.lastname: Pinto
authors.affiliation: Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Sergio F
authors.initials: SF
authors.lastname: Oliveira
authors.affiliation: Department of Life Sciences, University of Siena, Siena, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ietta
authors.affiliation: Department of Life Sciences, University of Siena, Siena, Italy.
authors.forename: Luana
authors.initials: L
authors.lastname: Paulesu
authors.affiliation: Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address: bevilacq@usp.br.
authors.forename: Estela
authors.initials: E
authors.lastname: Bevilacqua
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D003656:Decidua / Q000166:cytology*; D005260:Female; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000494:pharmacology*; D008431:Maternal-Fetal Exchange / Q000502:physiology; D051379:Mice; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D051736:Proto-Oncogene Proteins c-mdm2; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt