TOPK inhibits autophagy by phosphorylating ULK1 and promotes glioma resistance to TMZ.
Autophagy
/ genetics
Autophagy-Related Protein-1 Homolog
/ chemistry
Cell Line, Tumor
Drug Resistance, Neoplasm
/ genetics
Glioblastoma
/ drug therapy
HEK293 Cells
Humans
Intracellular Signaling Peptides and Proteins
/ chemistry
Mitogen-Activated Protein Kinase Kinases
/ genetics
Phosphorylation
/ genetics
Protein Domains
Protein Stability
Temozolomide
/ therapeutic use
Transfection
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
05 08 2019
05 08 2019
Historique:
received:
19
04
2019
accepted:
11
07
2019
revised:
02
07
2019
entrez:
6
8
2019
pubmed:
6
8
2019
medline:
14
7
2020
Statut:
epublish
Résumé
ULK1, the upper-most protein of the ULK1 complex, is emerging as a crucial node in autophagy induction. However, the regulation of ULK1 is not fully understood. In this study, we identified TOPK (T-LAK cell-originated protein kinase), an oncokinase, as a novel upstream kinase to phosphorylate ULK1. We found that TOPK could directly bind with and phosphorylate ULK1 at Ser469, Ser495, and Ser533. The phosphorylation of ULK1 at Ser469, Ser495, and Ser533 by TOPK decreased the activity and stability of ULK1. In addition, we want to examine the initiation of autophagy because the reduction activity of ULK1 reduces the occurrence of autophagy. We demonstrated that TOPK could inhibit the initiation and progression of autophagy in glioma cells. Furthermore, TOPK inhibition increased the sensitivity of glioma cells to temozolomide (TMZ). This discovery provides insight into the problem of TMZ-resistance in GBM treatment.
Identifiants
pubmed: 31378785
doi: 10.1038/s41419-019-1805-9
pii: 10.1038/s41419-019-1805-9
pmc: PMC6680050
doi:
Substances chimiques
Intracellular Signaling Peptides and Proteins
0
Autophagy-Related Protein-1 Homolog
EC 2.7.11.1
ULK1 protein, human
EC 2.7.11.1
Mitogen-Activated Protein Kinase Kinases
EC 2.7.12.2
PDZ-binding kinase
EC 2.7.12.2
Temozolomide
YF1K15M17Y
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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