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Localization of BCR-ABL to Stress Granules Contributes to Its Oncogenic Function

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Title: Localization of BCR-ABL to Stress Granules Contributes to Its Oncogenic Function
Authors: Kashiwagi, Sayaka Browse this author
Fujioka, Yoichiro Browse this author →KAKEN DB
Kondo, Takeshi Browse this author →KAKEN DB
Satoh, Aya O. Browse this author
Yoshida, Aiko Browse this author →KAKEN DB
Fujioka, Mari Browse this author
Sasajima, Hitoshi Browse this author
Amano, Maho Browse this author
Teshima, Takanori Browse this author →KAKEN DB
Ohba, Yusuke Browse this author →KAKEN DB
Keywords: BCR-ABL
subcellular localization
stress granule
Issue Date: 2019
Publisher: 一般社団法人 日本細胞生物学会(Japan Society for Cell Biology)
Journal Title: Cell structure and function
Volume: 44
Issue: 2
Start Page: 195
End Page: 204
Publisher DOI: 10.1247/csf.19033
Abstract: The oncogenic tyrosine kinase BCR-ABL activates a variety of signaling pathways and plays a causative role in the pathogenesis of chronic myelogenous leukemia (CML); however, the subcellular distribution of this chimeric protein remains controversial. Here, we report that BCR-ABL is localized to stress granules and that its granular localization contributes to BCR-ABL-dependent leukemogenesis. BCR-ABL-positive granules were not colocalized with any markers for membrane bound organelles but mere colocalized with HSP90a, a component of RNA granules. The number of such granules increased with thapsigargin treatment, confirming that the granules were stress granules. Given that treatment with the ABL kinase inhibitor imatinih and elimination of the N terminal region of BCR-ABL abolished granule formation, kinase activity and the coiled-coil domain are required for granule formation. Whereas wild-type BCR-ABL rescued the growth defect in IL-3-depleted Ba/F3 cells, mutant BCR-ABL lacking the N-terminal region failed to do so. Moreover, forced tetramerization of the N-terminus-deleted mutant could not restore the growth defect, indicating that granule formation, but not tetramerization, through its N-terminus is critical for BCR-ABL-dependent oncogenicity. Our findings together provide new insights into the pathogenesis of CML by BCR-ABL and open a window for developing novel therapeutic strategies for this disease.
Rights: https://creativecommons.org/licenses/by/4.0/
Type: article
URI: http://hdl.handle.net/2115/76729
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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