Atg7 Modulates p53 Activity to Regulate Cell Cycle and Survival During Metabolic Stress

Lee, In Hye; Kawai, Yoshichika; Fergusson, Marı́a M.; Rovira, Ilsa I.; Bishop, Alexander J.R.; Motoyama, Noboru; Cao, Liu; Finkel, Toren

doi:10.1126/science.1218395

Cited by 298 publications

(238 citation statements)

References 30 publications

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“…Importantly, knockdown of ATG7, an important autophagy-related protein, blocked the acquisition of the EMT phenotype. In order to confirm the role of ATG7 in TP53 function as reported by Lee et al, 37 we used BECN1 siRNA; these results further revealed the link between autophagy and the EMT in GBM cells. Previous studies have established that autophagy is an evolutionarily conserved, multistep lysosomal degradation process in which a cell digests intracellular organelles when it needs to 'self-cannibalize'.…”

Section: Discussionmentioning

confidence: 99%

MIR517C inhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation

Xiao

Liu

et al. 2015

Autophagy

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(2015) MIR517C inhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation, Autophagy, 11:12, 2213-2232, DOI: 10.1080/15548627.2015 LG, low glucose; MAP1LC3B/LC3B, microtubuleassociated protein 1 light chain 3B; MU, mutation; NC, negative control; NSC, neural stem cell; oe, overexpressing; OS, overall survival; PFS, progression-free survival; qRT-PCR, quantitative real-time reverse transcription polymerase chain reaction; SNAI2, Slug (snail family zinc finger 2); SNAI1, snail (snail family zinc finger 1); TEM, transmission electron microscopy; TMZ, temozolomide; VIM, vimentin; WT, wild type; ZEB1, zinc finger E-box binding homeobox 1.The epithelial-to-mesenchymal (-like) transition (EMT), a crucial embryonic development program, has been linked to the regulation of glioblastoma (GBM) progression and invasion. Here, we investigated the role of MIR517C/miR-517c, which belongs to the C19MC microRNA cluster identified in our preliminary studies, in the pathogenesis of GBM. We found that MIR517C was associated with improved prognosis in patients with GBM. Furthermore, following treatment with the autophagy inducer temozolomide (TMZ) and low glucose (LG), MIR517C degraded KPNA2 (karyopherin alpha 2 [RAG cohort 1, importin alpha 1]) and subsequently disturbed the nuclear translocation of TP53 in the GBM cell line U87 in vitro. Interestingly, this microRNA could inhibit autophagy and reduce cell migration and infiltration in U87 cells harboring wild-type (WT) TP53, but not in U251 cells harboring mutant (MU) TP53. Moreover, the expression of epithelial markers (i.e., CDH13/T-cadherin and CLDN1 [claudin 1]) increased, while the expression of mesenchymal markers (i.e., CDH2/N-cadherin, SNAI1/Snail, and VIM [vimentin]) decreased, indicating that the EMT status was blocked by MIR517C in U87 cells. Compared with MIR517C overexpression, MIR517C knockdown promoted infiltration of U87 cells to the surrounding structures in nude mice in vivo. The above phenotypic changes were also observed in TP53 +/+ and TP53 -/-HCT116 colon cancer cells. In summary, our study provided support for a link between autophagy and EMT status in WT TP53 GBM cells and provided evidence for the signaling pathway (MIR517C-KPNA2-cytoplasmic TP53) involved in attenuating autophagy and eliminating the increased migration and invasion during the EMT.

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Section: Discussionmentioning

confidence: 99%

MIR517C inhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation

Xiao

Liu

et al. 2015

Autophagy

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“…However, ATG7 acetylation is essential, because it is the last mandatory step of autophagy, and p300 down-regulation stimulates autophagy by inhibiting ATG7 acetylation (6). Interestingly, ATG7 has been shown to regulate p53 activity during starvation (25).…”

Section: Discussionmentioning

confidence: 99%

BAT3 modulates p300-dependent acetylation of p53 and autophagy-related protein 7 (ATG7) during autophagy

Sebti

Prébois

Pérez-Gracia

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Autophagy is regulated by posttranslational modifications, including acetylation. Here we show that HLA-B-associated transcript 3 (BAT3) is essential for basal and starvation-induced autophagy in embryonic day 18.5 BAT3 −/− mouse embryos and in mouse embryonic fibroblasts (MEFs) through the modulation of p300-dependent acetylation of p53 and ATG7. Specifically, BAT3 increases p53 acetylation and proautophagic p53 target gene expression, while limiting p300-dependent acetylation of ATG7, a mechanism known to inhibit autophagy. In the absence of BAT3 or when BAT3 is located exclusively in the cytosol, autophagy is abrogated, ATG7 is hyperacetylated, p53 acetylation is abolished, and p300 accumulates in the cytosol, indicating that BAT3 regulates the nuclear localization of p300. In addition, the interaction between BAT3 and p300 is stronger in the cytosol than in the nucleus and, during starvation, the level of p300 decreases in the cytosol but increases in the nucleus only in the presence of BAT3. We conclude that BAT3 tightly controls autophagy by modulating p300 intracellular localization, affecting the accessibility of p300 to its substrates, p53 and ATG7.degradation | signalisation | nucleo-cytoplasmic shuttling A utophagy allows the lysosomal degradation of intracellular macromolecules and organelles after their sequestration in a vacuole known as the autophagosome (1). Basal autophagy is a cytoplasmic quality control mechanism that limits the production of reactive oxygen species and genomic instability. Autophagy is also induced to improve cell survival under stress.Signaling pathways involved in the regulation of autophagy have been widely studied (2). Autophagy is modulated at two levels: (i) the molecular machinery involved in autophagosome biogenesis, dependent on specific genes known as Atg (AuTophaGy) genes, and (ii) the upstream signaling pathways (e.g., PI3K, MAPK, mTOR) that act on ATG proteins. Posttranslational modifications are crucial for the regulation of autophagy. The first example came from Y. Oshumi's laboratory with the discovery of the conjugation systems for the ATG5-ATG12 and ATG8-phosphatidylethanolamine complexes in yeast (3). Phosphorylation is probably the most thoroughly investigated posttranslational event in autophagy. It appears that modulation of acetylation also affects Atg gene expression or activity; for instance, acetylation of the Unc-51-like kinase 1 (ULK1) (mammalian homolog of ATG1) by the acetylase Tat interacting protein 60 kDa (TIP60) induces autophagy after growth factor deprivation (4). In yeast, ESA1-dependent acetylation of ATG3 is essential for its interaction with ATG8 and ATG8 lipidation (5). Conversely, acetylation of ATG5, ATG7, microtubule associated protein 1 light chain 3 (LC3), and ATG12 by the acetyltransferase p300 inhibits autophagy (6), whereas their deacetylation by Sirtuins 1 (SIRT1) stimulates autophagy (7).HLA-B-associated transcript 3 (BAT3) is a nucleo-cytoplasmic shuttling protein that contains, among other, a nuclear export signal (NES) and...

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“…1,2 On the other hand, dysfunctional autophagy via Atg7 conditional knock-out is considered as one of the failing cellular mechanisms involved in the pathogenesis of idiopathic Parkinson's Disease (PD). 3 So far, numerous evidences about the autophagy function have mainly concentrated on nervous system, such as, the differentiation of neuroepithelial cells or the neurodegeneration and behavioral deficits by Atg7 conditional knockout in mouse neurons.…”

Section: Introductionmentioning

confidence: 99%

Autophagy functions on EMT in gastrulation of avian embryo

Wang

et al. 2014

Cell Cycle

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y These authors contributed equally to this work.Keywords: autophagy, Atg7, EMT and chick embryo, gastrulation Abbreviations: 3-MA, 3-Methyladenine; BF, bright-field; DAPI, 49-6-Diamidino-2-phenylindole; EB, embryoid bodies; E-Cad, E-cadherin; EMTs, epithelial-mesenchymal transitions; GFP, green fluorescent protein; HN, Hensen's node; MAPILC3(LC3), microtubule-associated protein 1 light chain 3; mTOR, mammalian target of rapamycin; N-Cad, N-cadherin; NT, neural tube; PBS, phosphate-buffered saline; PCD, Programmed cell death; PD, idiopathic Parkinson's Disease; PI3K, phosphoinositide-3-kinase; PPIA, peptidylprolyl isomerase A; PS, primitive streak; RAPA, Rapamycin; RT-PCR, reverse transcription PCR; shh, sonic hedgehog.Autophagy is important for cell renewing for its contribution to the degradation of bulk cytoplasm, long-lived proteins, and entire organelles and its role in embryonic development is largely unknown. In our study, we investigated the function of autophagy in gastrulation of the chick embryo using both in vivo and in vitro approaches, especially in the EMT process, and we found that autophagy gene Atg7 was expressed on the apical side of the ectoderm and endoderm. Over-expression of Atg7 could enhance the expression of Atg8 and the E-cadherin, the latter of which is a crucial marker of the EMT process. We also found that the disturbance of autophagy could retard the development of chick embryos in HH4 with shorter primitive steak than that in the control group, which is a newly formed structure during EMT process. So we assumed that autophagy could affect EMT process by adhesion molecule expression. Moreover, more molecules, such as slug, chordin, shh et., which were all involved in EMT process, were detected to address the mechanism of this phenomena. We established that the inhibition of autophagy could cause developmental delay by affecting EMT process in gastrulation of chick embryos.

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Atg7 Modulates p53 Activity to Regulate Cell Cycle and Survival During Metabolic Stress

Cited by 298 publications

References 30 publications

MIR517C inhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation

MIR517C inhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation

BAT3 modulates p300-dependent acetylation of p53 and autophagy-related protein 7 (ATG7) during autophagy

Autophagy functions on EMT in gastrulation of avian embryo

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