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Myung, Kyungjae
Center for Genomic Integrity
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GCA links TRAF6-ULK1-dependent autophagy activation in resistant chronic myeloid leukemia

Author(s)
Han, Seung HunKorm, SovannarithHan, Ye GiChoi, Soo-YoungKim, Soo-HyunChung, Hee JinPark, KibeomKim, Jae-YoungMyung, KyungjaeLee, Joo-YongKim, HongtaeKim, Dong-Wook
Issued Date
2019-12
DOI
10.1080/15548627.2019.1596492
URI
https://scholarworks.unist.ac.kr/handle/201301/26647
Fulltext
https://www.tandfonline.com/doi/full/10.1080/15548627.2019.1596492
Citation
AUTOPHAGY, v.15, no.12, pp.2076 - 2090
Abstract
Imatinib is the first molecularly targeted compound for chronic myeloid leukemia (CML) capable to inhibit BCR-ABL kinase activity. However, recent clinical evidence indicates that a substantial proportion of CML patients exhibit BCR-ABL-dependent or independent resistance to imatinib. Despite the importance of imatinib resistance in CML, the underlying molecular mechanisms of this resistance are largely unknown. Here, we identified GCA (grancalcin) as a critical regulator of imatinib resistance in chronic phase CML via activation of autophagy. Mechanistically, we demonstrated that GCA activates TRAF6 ubiquitin ligase activity to induce Lys63 ubiquitination of ULK1, a crucial regulator of autophagy, resulting in its stabilization and activation. We also highlighted the role of GCA-TRAF6-ULK1 autophagy regulatory axis in imatinib resistance. Our findings represent the basis for novel therapeutic strategies against CML.
Publisher
TAYLOR & FRANCIS INC
ISSN
1554-8627
Keyword (Author)
Autophagychronic myeloid leukemia (CML)grancalcin (GCA)imatinib resistanceTRAF6ULK1
Keyword
CALCIUM-BINDING PROTEINBCR-ABLPHILADELPHIA-CHROMOSOMETYROSINE KINASEMONITORING AUTOPHAGYFOLLOW-UPGRANCALCINMTORTHERAPYPATIENTS RECEIVING IMATINIB

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