PMID- 24637094 OWN - NLM STAT- MEDLINE DCOM- 20141212 LR - 20211203 IS - 1873-7544 (Electronic) IS - 0306-4522 (Linking) VI - 268 DP - 2014 May 30 TI - Characterization of Gcf2/Lrrfip1 in experimental cerebral ischemia and its role as a modulator of Akt, mTOR and beta-catenin signaling pathways. PG - 48-65 LID - S0306-4522(14)00205-X [pii] LID - 10.1016/j.neuroscience.2014.02.051 [doi] AB - 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 beta-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. CI - Copyright (c) 2014 IBRO. Published by Elsevier Ltd. All rights reserved. FAU - Gubern, C AU - Gubern C AD - Grup de Recerca Cerebrovascular, Servei de Neurologia, Institut d'Investigacio Biomedica de Girona (IdIBGi) Dr. Josep Trueta, Hospital Universitari de Girona Dr. Josep Trueta, Avenida de Franca s/n, 17007 Girona, Spain. Electronic address: cgubern@idibgi.org. FAU - Camos, S AU - Camos S AD - Grup de Recerca Cerebrovascular, Servei de Neurologia, Institut d'Investigacio Biomedica de Girona (IdIBGi) Dr. Josep Trueta, Hospital Universitari de Girona Dr. Josep Trueta, Avenida de Franca s/n, 17007 Girona, Spain. FAU - Hurtado, O AU - Hurtado O AD - Unidad de Investigacion Neurovascular, Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Avenida Complutense s/n, 28040 Madrid, Spain. FAU - Rodriguez, R AU - Rodriguez R AD - Grup de Recerca Cerebrovascular, Servei de Neurologia, Institut d'Investigacio Biomedica de Girona (IdIBGi) Dr. Josep Trueta, Hospital Universitari de Girona Dr. Josep Trueta, Avenida de Franca s/n, 17007 Girona, Spain. FAU - Romera, V G AU - Romera VG AD - Unidad de Investigacion Neurovascular, Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Avenida Complutense s/n, 28040 Madrid, Spain. FAU - Sobrado, M AU - Sobrado M AD - Unidad de Investigacion Neurovascular, Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Avenida Complutense s/n, 28040 Madrid, Spain. FAU - Canadas, R AU - Canadas R AD - Unidad de Investigacion Neurovascular, Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Avenida Complutense s/n, 28040 Madrid, Spain. FAU - Moro, M A AU - Moro MA AD - Unidad de Investigacion Neurovascular, Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Avenida Complutense s/n, 28040 Madrid, Spain. FAU - Lizasoain, I AU - Lizasoain I AD - Unidad de Investigacion Neurovascular, Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Avenida Complutense s/n, 28040 Madrid, Spain. FAU - Serena, J AU - Serena J AD - Grup de Recerca Cerebrovascular, Servei de Neurologia, Institut d'Investigacio Biomedica de Girona (IdIBGi) Dr. Josep Trueta, Hospital Universitari de Girona Dr. Josep Trueta, Avenida de Franca s/n, 17007 Girona, Spain. FAU - Mallolas, J AU - Mallolas J AD - Grup de Recerca Cerebrovascular, Servei de Neurologia, Institut d'Investigacio Biomedica de Girona (IdIBGi) Dr. Josep Trueta, Hospital Universitari de Girona Dr. Josep Trueta, Avenida de Franca s/n, 17007 Girona, Spain. Electronic address: judithmallolas@cofgi.org. FAU - Castellanos, M AU - Castellanos M AD - Grup de Recerca Cerebrovascular, Servei de Neurologia, Institut d'Investigacio Biomedica de Girona (IdIBGi) Dr. Josep Trueta, Hospital Universitari de Girona Dr. Josep Trueta, Avenida de Franca s/n, 17007 Girona, Spain. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140314 PL - United States TA - Neuroscience JT - Neuroscience JID - 7605074 RN - 0 (Ctnnb1 protein, rat) RN - 0 (Excitatory Amino Acid Transporter 2) RN - 0 (LRRFIP1 protein, rat) RN - 0 (RNA Isoforms) RN - 0 (RNA-Binding Proteins) RN - 0 (Slc1a2 protein, rat) RN - 0 (beta Catenin) RN - 3KX376GY7L (Glutamic Acid) RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Astrocytes/metabolism MH - Brain/metabolism MH - Brain Ischemia/etiology/*metabolism MH - Cells, Cultured MH - Cytoplasm/metabolism MH - Excitatory Amino Acid Transporter 2/metabolism MH - Gene Knockdown Techniques MH - Glutamic Acid/metabolism MH - Infarction, Middle Cerebral Artery/complications/metabolism MH - Male MH - Neurons/metabolism MH - Proto-Oncogene Proteins c-akt/*metabolism MH - RNA Isoforms/metabolism MH - RNA-Binding Proteins/genetics/*metabolism MH - Rats, Inbred F344 MH - Rats, Wistar MH - Signal Transduction MH - TOR Serine-Threonine Kinases/*metabolism MH - Up-Regulation MH - beta Catenin/*metabolism OTO - NOTNLM OT - GLT-1 OT - Lrrfip1 OT - MCAO OT - OGD OT - astrocytes OT - stroke EDAT- 2014/03/19 06:00 MHDA- 2014/12/17 06:00 CRDT- 2014/03/19 06:00 PHST- 2013/10/26 00:00 [received] PHST- 2014/02/03 00:00 [revised] PHST- 2014/02/27 00:00 [accepted] PHST- 2014/03/19 06:00 [entrez] PHST- 2014/03/19 06:00 [pubmed] PHST- 2014/12/17 06:00 [medline] AID - S0306-4522(14)00205-X [pii] AID - 10.1016/j.neuroscience.2014.02.051 [doi] PST - ppublish SO - Neuroscience. 2014 May 30;268:48-65. doi: 10.1016/j.neuroscience.2014.02.051. Epub 2014 Mar 14.