title: Activation of ERK/IER3/PP2A-B56γ-positive feedback loop in lung adenocarcinoma by allelic deletion of B56γ gene.
abstract: In order to investigate the involvement of the IER3/PP2A-B56γ/ERK-positive feedback loop, which leads to sustained phosphorylation/activation of ERK in carcinogenesis, we immunohistochemically examined the expression of IER3 and phosphorylated ERK in lung tumor tissues. IER3 was overexpressed in all cases of adenocarcinomas examined, but was not overexpressed in squamous cell carcinomas. Phosphorylated ERK (pERK) was also overexpressed in almost all adenocarcinomas. EGFR and RAS, whose gene product is located upstream of ERK, were sequenced. Activating mutation of EGFR, which is a possible cause of overexpression of IER3 and pERK, was found only in 5 adenocarcinomas (42%). No mutation of RAS was found. We further examined the sequences of all exons of B56γ gene (PPP2R5C) and IER3, but no mutation was found. Using a single nucleotide insertion in intron 1 of PPP2R5C, which was found in the process of sequencing, allelic deletion of PPP2R5C was examined. Eight cases were informative (67%), and the deletion was found in 4 of them (50%). Three cases having deletion of PPP2R5C did not have EGFR mutation. Finally, PPP2R5C deletion or EGFR mutation that could be responsible for IER3/pERK overexpression was found in at least 8 cases (67% or more). This is the first report of a high incidence of deletion of PPP2R5C in human carcinomas.
authors.affiliation: Department of Thoracic, Cardiovascular and General Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-8640, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ito
authors.affiliation: Department of Clinical Laboratory Medicine, Graduate School of Health Sciences, Kanazawa University, Kanazawa 920-0942, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Ozaki
authors.affiliation: Department of Anatomy, Faculty of Medical Sciences, Naresuan University, Phitsanulok 65000, Thailand.
authors.forename: Rachanee
authors.initials: R
authors.lastname: Chanasong
authors.affiliation: Department of Clinical Laboratory Medicine, Graduate School of Health Sciences, Kanazawa University, Kanazawa 920-0942, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Mizutani
authors.affiliation: Department of Pathology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-8640, Japan.
authors.forename: Takeru
authors.initials: T
authors.lastname: Oyama
authors.affiliation: Department of Clinical Laboratory Medicine, Graduate School of Health Sciences, Kanazawa University, Kanazawa 920-0942, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakurai
authors.affiliation: Department of Thoracic, Cardiovascular and General Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-8640, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Matsumoto
authors.affiliation: Department of Thoracic, Cardiovascular and General Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-8640, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Takemura
authors.affiliation: Department of Clinical Laboratory Medicine, Graduate School of Health Sciences, Kanazawa University, Kanazawa 920-0942, Japan.
authors.forename: Ei
authors.initials: E
authors.lastname: Kawahara
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000077192:Adenocarcinoma of Lung; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001483:Base Sequence; D004252:DNA Mutational Analysis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D025461:Feedback, Physiological; D017353:Gene Deletion; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000378:metabolism; D016254:Mutagenesis, Insertional; D009154:Mutation; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000235:genetics* / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D015533:Transcriptional Activation
chemical_list: D051017:Apoptosis Regulatory Proteins; C099815:IER3 protein, human; D008565:Membrane Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; C503981:PPP2R5C protein, human; D054648:Protein Phosphatase 2