title: RalA, a GTPase targeted by miR-181a, promotes transformation and progression by activating the Ras-related signaling pathway in chronic myelogenous leukemia.
abstract: BCR/ABL is a well-known activator of multiple signaling pathways. RalA, a Ras downstream signaling molecule and a small GTPase, plays an important role in Bcr-Abl-induced leukemogenesis but the exact mechanism remains elusive. Here, we show that RalA GTPase activity is commonly high in chronic myelogenous leukemia (CML) cell lines and patient samples. Overexpression of RalA results in malignant transformation and progression, and induces resistance to imatinib (IM) in BaF3 and K562 cell lines. RalA reduced survival and led to IM resistance in a xenografted mouse model. Ablation of RalA by either siRNA or miR-181a, a RalA targeting microRNA, attenuated the malignant phenotypes in K562 cells. RBC8, a selective Ral inhibitor, enhanced the inhibitory effects of IM in K562, KCL22 and BaF3-P210 cells. Interestingly, the phospho-specific protein microarray assay revealed that multiple phosphorylation signal proteins were decreased by RalA inhibition, including SAPK, JNK, SRC, VEGFR2, P38 MAPK, c-Kit, JunB, and Keratin18. Among them, P38 MAPK and SAPK/JNK are Ras downstream signaling kinases. Taken together, RalA GTPase might be an important oncogene activating the Ras-related signaling pathway in CML.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China.|Insititute of Chinese Integrative Medicine, Medical College of Jinan University, Guangzhou 510632, China.
authors.forename: Chunming
authors.initials: C
authors.lastname: Gu
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China.
authors.forename: Maoxiao
authors.initials: M
authors.lastname: Feng
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Yin
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China.
authors.forename: Xiaochuang
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China.
authors.forename: Juhua
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Clinical Medicine, Medical College of Jinan University, Guangzhou 510632, China.
authors.forename: Tianfu
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Clinical Medicine, Medical College of Jinan University, Guangzhou 510632, China.
authors.forename: Ruirui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China.|Insititute of Chinese Integrative Medicine, Medical College of Jinan University, Guangzhou 510632, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Fei
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D020725:ral GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D016044:Fusion Proteins, bcr-abl; C492198:RALA protein, human; D020725:ral GTP-Binding Proteins; D018631:ras Proteins
keywords: RalA GTPases; Ras signaling pathway; chronic myelogenous leukemia; imatinib; malignant transformation