title: ATM-mediated PTEN phosphorylation promotes PTEN nuclear translocation and autophagy in response to DNA-damaging agents in cancer cells.
abstract: PTEN (phosphatase and tensin homolog), a tumor suppressor frequently mutated in human cancer, has various cytoplasmic and nuclear functions. PTEN translocates to the nucleus from the cytoplasm in response to oxidative stress. However, the mechanism and function of the translocation are not completely understood. In this study, topotecan (TPT), a topoisomerase I inhibitor, and cisplatin (CDDP) were employed to induce DNA damage. The results indicate that TPT or CDDP activates ATM (ATM serine/threonine kinase), which phosphorylates PTEN at serine 113 and further regulates PTEN nuclear translocation in A549 and HeLa cells. After nuclear translocation, PTEN induces autophagy, in association with the activation of the p-JUN-SESN2/AMPK pathway, in response to TPT. These results identify PTEN phosphorylation by ATM as essential for PTEN nuclear translocation and the subsequent induction of autophagy in response to DNA damage.
authors.affiliation: a State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Cancer Center; Sun Yat-sen University ; Guangzhou , China.
authors.forename: Jing-Hong
authors.initials: JH
authors.lastname: Chen
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Wen-Dan
authors.initials: WD
authors.lastname: Chen
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Li
authors.forename: Xiao-Qi
authors.initials: XQ
authors.lastname: Wu
authors.forename: Rong
authors.initials: R
authors.lastname: Deng
authors.forename: Lin
authors.initials: L
authors.lastname: Jiao
authors.forename: Xuan
authors.initials: X
authors.lastname: Li
authors.forename: Jiao
authors.initials: J
authors.lastname: Ji
authors.forename: Gong-Kan
authors.initials: GK
authors.lastname: Feng
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
authors.forename: Jian-Wei
authors.initials: JW
authors.lastname: Jiang
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Zhu
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology; D019772:Topotecan / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D059004:Topoisomerase I Inhibitors; D025521:Tumor Suppressor Proteins; D019772:Topotecan; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D002945:Cisplatin
keywords: AKT/PKB, v-akt murine thymoma viral oncogene homolog; AMPK, protein kinase, AMP-activated; ATG, autophagy-related; ATM; ATM, ATM serine/threonine kinase; Baf.A1, bafilomycin A1; CASP3, caspase 3, apoptosis-related cysteine peptidase; CCND1, cyclin D1; CDDP, cisplatin; CENPC/CENP-C, centromere protein C; CITED1/p300/CBP, Cbp/p300-interacting transactivator, with Glu/Asp-rich C-terminal domain, 1; CSNK2/CK2, casein kinase 2; DNA damage; DSBs, DNA double-strand breaks; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFP, green fluorescent protein; GLTSCR2/PICT-1, glioma tumor suppressor candidate region gene 2; GSK3B, glycogen synthase kinase 3 β; GST, glutathione S-transferase; H2A histone family; H2AFX; JUN; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MTORC1, mechanistic target of rapamycin complex 1; MVP, major vault protein; NC, normal control; NEDD4, neural precursor cell expressed, developmentally down-regulated 4, E3 ubiquitin protein ligase; PAGE, polyacrylamide gel electrophoresis; PARP, poly (ADP-ribose) polymerase 1; PI3K, phosphoinositide 3-kinase; PMSF, phenylmethanesulfonyl fluoride; PPase, protein phosphatase; PTEN; PTEN, phosphatase and tensin homolog; PtdIns(3, 4, 5)P3, phosphatidylinositol (3, 4, 5)-trisphosphate; RAD51, RAD51 recombinase; RPS6KB/p70S6K; SDS, sodium dodecyl sulfate; SESN2, sestrin 2; SQSTM1/p62, sequestosome 1; TP53, tumor protein p53; TPT, topotecan; TUBA4A, tubulin, α, 4a; WT, wild type; YFP, yellow fluorescent protein; autophagy; jun proto-oncogene; member X; ribosomal protein S6 kinase, 70kDa; siRNA, small interfering RNA; topotecan