title: Rab15 expression correlates with retinoic acid-induced differentiation of neuroblastoma cells.
abstract: Neuroblastoma is the most common extracranial solid tumor in children and accounts for 15% of pediatric cancer deaths. Although retinoic acid (RA) is currently used to treat high-risk neuroblastoma patients in the clinic, RA-responsiveness is variable and unpredictable. Since no alterations in the RA-signaling pathway have been found in neuroblastoma cells, molecules correlated with RA-induced differentiation will provide predictive markers of RA-responsiveness for clinical use. The Rab family of small G proteins are key regulators of membrane traffic and play a critical role in cell differentiation and cancer progression. Although an increasing number of cancer-associated alternative splicing events have been identified, alternative splicing of Rab proteins remains to be characterized in neuroblastoma. In the present study, we focused on Rab15 that was originally identified as a brain-specific Rab protein and regulates the endocytic recycling pathway. We identified alternatively spliced Rab15 isoforms designated as Rab15CN and Rab15AN in neuroblastoma cells. Rab15CN was composed of 7 exons encoding 212 amino acids and showed brain-specific expression. Alternative splicing of exon 4 generated Rab15AN that was predicted to encode 208 amino acids and was predominantly expressed in testis. RA induced neuronal differentiation of neuroblastoma BE(2)-C cells and specifically up-regulated Rab15CN expression. Reciprocally, RA-induced differentiation was observed in Rab15CN-expressing BE(2)-C cells in preference to Rab15AN-expressing BE(2)-C cells. Furthermore, Rab15CN expression was also specifically up-regulated during RA-induced differentiation of newly established neuroblastoma cells from high-risk patients. These results suggest that Rab15 expression correlates with RA-induced differentiation of neuroblastoma cells.
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, and Department of Hematology and Oncology, Hyogo Children's Hospital, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. nnishi@med.kobe-u.ac.jp
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Nishimura
authors.forename: Thi
authors.initials: T
authors.lastname: Van Huyen Pham
authors.forename: Tri Budi
authors.initials: TB
authors.lastname: Hartomo
authors.forename: Myeong Jin
authors.initials: MJ
authors.lastname: Lee
authors.forename: Daiichiro
authors.initials: D
authors.lastname: Hasegawa
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takeda
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Kawasaki
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kosaka
authors.forename: Tomoto
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Satoru
authors.initials: S
authors.lastname: Morikawa
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Ikuko
authors.initials: I
authors.lastname: Kubokawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Mori
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yanai
authors.forename: Akira
authors.initials: A
authors.lastname: Hayakawa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takeshima
authors.forename: Hisahide
authors.initials: H
authors.lastname: Nishio
authors.forename: Masafumi
authors.initials: M
authors.lastname: Matsuo
mesh_terms: D017398:Alternative Splicing; D017209:Apoptosis; D002454:Cell Differentiation; D002648:Child; D002675:Child, Preschool; D005091:Exons; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence / Q000379:methods; D009447:Neuroblastoma / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D020033:Protein Isoforms; D020691:rab GTP-Binding Proteins / Q000096:biosynthesis*
chemical_list: D020033:Protein Isoforms; D020691:rab GTP-Binding Proteins; C509341:RAB15 protein, human