Autophagy regulation by p53

Maiuri, Maria Chiara; Galluzzi, Lorenzo; Morselli, Eugenia; Kepp, Oliver; Malik, Shoaib Ahmad

doi:10.1016/j.ceb.2009.12.001

Cited by 442 publications

(390 citation statements)

References 47 publications

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“…However, in the cytoplasm, TP53 suppresses the induction of autophagy. 50 Thus, downregulation of KPNA2 can interfere with autophagy through disruption of the nuclear import of TP53, which was also shown in our current study. Therefore, we suggest that a pathway involving MIR517C, KPNA2 and TP53 is involved in the regulation of autophagy and the EMT (Fig.…”

Section: Discussionsupporting

confidence: 50%

“…54 Although the details of these mechanisms are still unclear, cytoplasmic TP53 has been widely reported to inhibit autophagy through extranuclear, transcriptionindependent mechanisms. 50 Although in this study we only used U87 cells harboring WT TP53 and U251 harboring MU TP53 as GBM model cells, TP53 +/+ and TP53 -/-HCT116 cells were used to demonstrate the WT TP53-dependent function of MIR517C and KPNA2 in the single altered cell background. Furthermore, we are planning to design several mutants in the functional domains of TP53 in order to investigate the details of the MIR517C-KPNA2-TP53 pathway in the regulation of autophagy and the EMT in GBM.…”

Section: Discussionmentioning

confidence: 99%

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MIR517Cinhibits 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: Discussionsupporting

confidence: 50%

Section: Discussionmentioning

confidence: 99%

MIR517Cinhibits 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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“…Many links exist between autophagy and cancer (10)(11)(12)(13)(14). An anticancer role for autophagy is implied from its activation by tumor suppressor proteins, including Beclin 1, tuberous sclerosis (TSC)1, TSC2, death associated protein-kinase 1 (DAPK1), and alternate reading frame (ARF).…”

mentioning

confidence: 99%

p53-dependent regulation of autophagy protein LC3 supports cancer cell survival under prolonged starvation

Scherz-Shouval¹,

Weidberg

Gonen³

et al. 2010

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

206

151

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The p53 tumor suppressor is mutated in a high percentage of human tumors. However, many other tumors retain wild-type (wt) p53 expression, raising the intriguing possibility that they actually benefit from it. Recent studies imply a role for p53 in regulation of autophagy, a catabolic pathway by which eukaryotic cells degrade and recycle macromolecules and organelles, particularly under conditions of nutrient deprivation. Here, we show that, in many cell types, p53 confers increased survival in the face of chronic starvation. We implicate regulation of autophagy in this effect. In HCT116 human colorectal cancer cells exposed to prolonged nutrient deprivation, the endogenous wt p53 posttranscriptionally down-regulates LC3, a pivotal component of the autophagic machinery. This enables reduced, yet sustainable autophagic flux. Loss of p53 impairs autophagic flux and causes excessive LC3 accumulation upon starvation, culminating in apoptosis. Thus, p53 increases cell fitness by maintaining better autophagic homeostasis, adjusting the rate of autophagy to changing circumstances. We propose that some cancer cells retain wt p53 to benefit from the resultant increased fitness under limited nutrient supply.apoptosis | posttranscriptional regulation

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“…It is widely accepted that the tumor suppressor p53 regulates autophagy depending upon is subcellular localization [49]. Normal levels of p53 maintain a tonic inhibition of autophagy; autophagy is induced via a reduction in cytoplasmic p53 levels [61].…”

Section: Discussionmentioning

confidence: 99%

“…The effect of TNFa and IFNc given in combination reflected that of cells treated with either cytokine alone and therefore, we did not pursue the effects of these cytokines in combination. It is widely accepted that the tumor suppressor p53 regulates autophagy [49]. Since Caco2-BBE cells have mutated p53 [50], we assessed the involvement of p53 in autophagy induction by TNFa and IFNc in wild-type (WT) and p53 null HCT116 colonic epithelial cells.…”

Section: Phb Protein Expression Inversely Correlates With Cytokine-inmentioning

confidence: 99%

320 Prohibitin 1 Modulates Mitochondrial Stress-Related Autophagy in Human Colonic Epithelial Cells

Kathiria¹,

Butcher²,

Feagins³

et al. 2012

Gastroenterology

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Autophagy regulation by p53

Cited by 442 publications

References 47 publications

MIR517Cinhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation

MIR517Cinhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation

p53-dependent regulation of autophagy protein LC3 supports cancer cell survival under prolonged starvation

320 Prohibitin 1 Modulates Mitochondrial Stress-Related Autophagy in Human Colonic Epithelial Cells

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