title: Characterization of Gcf2/Lrrfip1 in experimental cerebral ischemia and its role as a modulator of Akt, mTOR and β-catenin signaling pathways.
abstract: Leucine-rich repeat in Flightless-1 interaction protein 1 (Lrrfip1) is an up-regulated protein after cerebral ischemia whose precise role in the brain both in healthy and ischemic conditions is unclear. Different Lrrfip1 isoforms with distinct roles have been reported in human and mouse species. The present study aimed to analyze the Lrrfip1 transcriptional variants expressed in rat cortex, to characterize their expression patterns and subcellular location after ischemia, and to define their putative role in the brain. Five transcripts were identified and three of them (Lrrfip1, CRA_g and CRA_a' (Fli-I leucine-rich repeat associated protein 1 - Flap-1)) were analyzed by quantitative real-time polymerase chain reaction (qPCR). All the transcripts were up-regulated and showed differential expression patterns after in vivo and in vitro ischemia models. The main isoform, Lrrfip1, was found to be up-regulated from the acute to the late phases of ischemia in the cytoplasm of neurons and astrocytes of the peri-infarct area. This study demonstrates that Lrrfip1 activates β-catenin, Akt, and mammalian target of rapamycin (mTOR) proteins in astrocytes and positively regulates the expression of the excitatory amino acid transporter subtype 2 (GLT-1). Our findings point to Lrrfip1 as a key brain protein that regulates pro-survival pathways and proteins and encourages further studies to elucidate its role in cerebral ischemia as a potential target to prevent brain damage and promote functional recovery after stroke.
authors.affiliation: Grup de Recerca Cerebrovascular, Servei de Neurologia, Institut d'Investigació Biomèdica de Girona (IdIBGi) Dr. Josep Trueta, Hospital Universitari de Girona Dr. Josep Trueta, Avenida de França s/n, 17007 Girona, Spain. Electronic address: cgubern@idibgi.org.
authors.forename: C
authors.initials: C
authors.lastname: Gubern
authors.affiliation: Grup de Recerca Cerebrovascular, Servei de Neurologia, Institut d'Investigació Biomèdica de Girona (IdIBGi) Dr. Josep Trueta, Hospital Universitari de Girona Dr. Josep Trueta, Avenida de França s/n, 17007 Girona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Camós
authors.affiliation: Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Avenida Complutense s/n, 28040 Madrid, Spain.
authors.forename: O
authors.initials: O
authors.lastname: Hurtado
authors.affiliation: Grup de Recerca Cerebrovascular, Servei de Neurologia, Institut d'Investigació Biomèdica de Girona (IdIBGi) Dr. Josep Trueta, Hospital Universitari de Girona Dr. Josep Trueta, Avenida de França s/n, 17007 Girona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Rodríguez
authors.affiliation: Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Avenida Complutense s/n, 28040 Madrid, Spain.
authors.forename: V G
authors.initials: VG
authors.lastname: Romera
authors.affiliation: Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Avenida Complutense s/n, 28040 Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Sobrado
authors.affiliation: Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Avenida Complutense s/n, 28040 Madrid, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Cañadas
authors.affiliation: Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Avenida Complutense s/n, 28040 Madrid, Spain.
authors.forename: M A
authors.initials: MA
authors.lastname: Moro
authors.affiliation: Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Avenida Complutense s/n, 28040 Madrid, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Lizasoain
authors.affiliation: Grup de Recerca Cerebrovascular, Servei de Neurologia, Institut d'Investigació Biomèdica de Girona (IdIBGi) Dr. Josep Trueta, Hospital Universitari de Girona Dr. Josep Trueta, Avenida de França s/n, 17007 Girona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Serena
authors.affiliation: Grup de Recerca Cerebrovascular, Servei de Neurologia, Institut d'Investigació Biomèdica de Girona (IdIBGi) Dr. Josep Trueta, Hospital Universitari de Girona Dr. Josep Trueta, Avenida de França s/n, 17007 Girona, Spain. Electronic address: judithmallolas@cofgi.org.
authors.forename: J
authors.initials: J
authors.lastname: Mallolas
authors.affiliation: Grup de Recerca Cerebrovascular, Servei de Neurologia, Institut d'Investigació Biomèdica de Girona (IdIBGi) Dr. Josep Trueta, Hospital Universitari de Girona Dr. Josep Trueta, Avenida de França s/n, 17007 Girona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Castellanos
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000209:etiology / Q000378:metabolism*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D055785:Gene Knockdown Techniques; D018698:Glutamic Acid / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D059368:RNA Isoforms / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495268:Ctnnb1 protein, rat; D027342:Excitatory Amino Acid Transporter 2; C583985:LRRFIP1 protein, rat; D059368:RNA Isoforms; D016601:RNA-Binding Proteins; C493395:Slc1a2 protein, rat; D051176:beta Catenin; D018698:Glutamic Acid; C546845:mTOR protein, rat; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: GLT-1; Lrrfip1; MCAO; OGD; astrocytes; stroke