Induction of genomic instability and activation of autophagy in artificial human aneuploid cells

Ariyoshi, Kentaro; Miura, Tomisato; Kasai, Kosuke; Fujishima, Yohei; Oshimura, Mitsuo; Yoshida, Mitsuaki A.

doi:10.1016/j.mrfmmm.2016.06.001

Cited by 29 publications

(21 citation statements)

References 28 publications

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“…In this context, autophagy deficiency leads to genome instability under metabolic stress in these mouse mammary epithelial cells (123). Artificially aneuploid mouse cells showed increased autophagy to protect cells from genome instability (124).…”

Section: Hallmarks Of Aging: An Autophagic Viewmentioning

confidence: 99%

Hallmarks of Aging: An Autophagic Perspective

2019

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Autophagy is a major protein turnover pathway by which cellular components are delivered into the lysosomes for degradation and recycling. This intracellular process is able to maintain cellular homeostasis under stress conditions, and its dysregulation could lead to the development of physiological alterations. The autophagic activity has been found to decrease with age, likely contributing to the accumulation of damaged macromolecules and organelles during aging. Interestingly, failure of the autophagic process has been reported to worsen aging-associated diseases, such as neurodegeneration or cancer, among others. Likewise, it has been proposed in different organisms that maintenance of a proper autophagic activity contributes to extending longevity. In this review, we discuss recent papers showing the impact of autophagy on cell activity and age-associated diseases, highlighting the relevance of this process to the hallmarks of aging. Thus, understanding how autophagy plays an important role in aging opens new avenues for the discovery of biochemical and pharmacological targets and the development of novel anti-aging therapeutic approaches.

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Section: Hallmarks Of Aging: An Autophagic Viewmentioning

confidence: 99%

Hallmarks of Aging: An Autophagic Perspective

2019

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“…Studies showed that miR-124-3p inhibitesbreast cancercell progression by decreased cellular autophagy [ 20 ] and autophagy is increased in the skeletal muscle of cachectic cancer patients [ 21 ]. Furthermore, autophagy-related SQSTM1/p62 is involved in cellular DNA damage response [ 22 ] and autophagy descreased the abnormal chromosome number [ 23 ]. Moreover, some reports showed autophagy was associated with cellular beta 1-integrin-c-Met signaling [ 24 ], NAD + −dependent histone deacetylase Sirt1 [ 25 ], miR212-SIRT1 pathway and cellular senescence [ 26 ], Choline dehydrogenase -SQSTM1/p62 [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

Long noncoding RNA HULC accelerates liver cancer by inhibiting PTEN via autophagy cooperation to miR15a

et al. 2018

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BackgroundLong noncoding RNA HULC is highly up-regulation in human hepatocellular carcinoma (HCC). However, the functions of HULC in hepatocarcinogenesis remains unclear.MethodsRT-PCR, Western blotting, Chromatin immunoprecipitation (CHIP) assay, RNA Immunoprecipitation (RIP) and tumorignesis test in vitro and in vivo were performed.ResultsHULC is negatively associated with expression of PTEN or miR15a in patients of human liver cancer. Moreover, HULC accelerates malignant progression of liver cancer cells in vitro and in vivo. Mechanistically, HULC increasesthe expression of P62 via decreasing mature miR15a. On the other hand, excessive HULC increases the expression of LC3 on the level of transcription and then activates LC3 through Sirt1 (a deacetylase). Notably, HULC enhanced the interplay between LC3 and ATG3. Furthermore, HULC also increases the expression of becline-1(autophagy related gene). Therefore, HULC increases the cellular autophagy by increasing LC3II dependent on Sirt1.Noteworthy, excessive HULC reduces the expression of PTEN, β-catenin and enhances the expression of SAPK/JUNK, PKM2, CDK2, NOTCH1, C-Jun in liver cancer cells. Of significance, our observations also revealed that HULC inhibited PTEN through ubiquitin–proteasome system mediated by autophagy-P62.Ultimately,HULC activates AKT-PI3K-mTOR pathway through inhibiting PTEN in human liver cancer cells.ConclusionsThis study elucidates a novel mechanism that lncRNA HULC produces a vital function during hepatocarcinogenesis.

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“…Recently developed aneuploid model systems in several different species have accelerated research on the effects of aneuploidy per se. The physiological changes in response to an unbalanced karyotype are multifold, including impaired proliferation, replication stress and proteotoxic stress that is characterized by changes in protein stoichiometry, reduced protein folding capacity and by activation of autophagy [4][5][6][7][8][9][10][11][12][13]. The physiological response to aneuploidy goes hand in hand with a transcriptional response that is manifested in a conserved pathway deregulation [14,15].…”

Section: Introductionmentioning

confidence: 99%

The deregulated microRNAome contributes to the cellular response to aneuploidy

et al. 2018

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Background: Aneuploidy, or abnormal chromosome numbers, severely alters cell physiology and is widespread in cancers and other pathologies. Using model cell lines engineered to carry one or more extra chromosomes, it has been demonstrated that aneuploidy per se impairs proliferation, leads to proteotoxic as well as replication stress and triggers conserved transcriptome and proteome changes. Results: In this study, we analysed for the first time miRNAs and demonstrate that their expression is altered in response to chromosome gain. The miRNA deregulation is independent of the identity of the extra chromosome and specific to individual cell lines. By cross-omics analysis we demonstrate that although the deregulated miRNAs differ among individual aneuploid cell lines, their known targets are predominantly associated with cell development, growth and proliferation, pathways known to be inhibited in response to chromosome gain. Indeed, we show that up to 72% of these targets are downregulated and the associated miRNAs are overexpressed in aneuploid cells, suggesting that the miRNA changes contribute to the global transcription changes triggered by aneuploidy. We identified hsa-miR-10a-5p to be overexpressed in majority of aneuploid cells. Hsa-miR-10a-5p enhances translation of a subset of mRNAs that contain so called 5'TOP motif and we show that its upregulation in aneuploids provides resistance to starvation-induced shut down of ribosomal protein translation.

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Induction of genomic instability and activation of autophagy in artificial human aneuploid cells

Cited by 29 publications

References 28 publications

Hallmarks of Aging: An Autophagic Perspective

Hallmarks of Aging: An Autophagic Perspective

Long noncoding RNA HULC accelerates liver cancer by inhibiting PTEN via autophagy cooperation to miR15a

The deregulated microRNAome contributes to the cellular response to aneuploidy

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