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• W2146122012 abstract "HomeCirculation ResearchVol. 111, No. 8Impaired G1-Arrest, Autophagy, and Apoptosis in Atg7-Knockout Mice Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBImpaired G1-Arrest, Autophagy, and Apoptosis in Atg7-Knockout Mice Shun Kageyama and Masaaki Komatsu Shun KageyamaShun Kageyama From the Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan. Search for more papers by this author and Masaaki KomatsuMasaaki Komatsu From the Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan. Search for more papers by this author Originally published28 Sep 2012https://doi.org/10.1161/CIRCRESAHA.112.280768Circulation Research. 2012;111:962–964Atg7 Modulates p53 Activity to Regulate Cell Cycle andSurvival During Metabolic StressLee et alScience. 2012;336:225–228.Exit from cell division cycle, induction of autophagy, and activation of apoptosis in response to metabolic stress occur simultaneously or sequentially. However, the molecular interrelation(s) between these intracellular events remains obscure. Recent work by Finkel et al1 provides evidence that Atg7, an autophagy-related protein, regulates G1-arrest by interacting with p53 and that p53-mediated apoptosis is activated under autophagy-deficient conditions.Macroautophagy (hereafter referred to as autophagy) is a self-eating system conserved among eukaryotes. In this process, cellular components, including organelles, are entrapped into a double-membrane structure called the autophagosome and then degraded by lysosomal hydrolases (Figure 1).2 In addition to its role in supplying amino acids in response to nutrient starvation, autophagy is involved in quality control to maintain cell health. Thus, inactivation of autophagy results in the accumulation of cytoplasmic protein aggregates of misfolded proteins and damaged and degenerated organelles, which compromise cell function and often result in life-threatening diseases.2Download figureDownload PowerPointFigure 1. Autophagy. The initial steps of autophagy include the formation and subsequent elongation of the isolation membrane. The isolation membrane then enwraps various cytoplasmic constituents, such as organelles, until its edges fuse with each other to form a double-membrane structure called the autophagosome. Finally, the outer membrane of the autophagosome fuses with the lysosome and endosome. The sequestered cytoplasmic components, together with the inner membrane of the autophagosome, are completely degraded by lysosomal hydrolases (Mizushima et al4 for details on the molecular players). The ubiquitin-like modifier, LC3, covalently conjugates with phosphatidylethanolamine (PE) through an enzymatic cascade consisting of Atg7 (E1-like enzyme), Atg3 (E2-like enzyme), and Atg12-Atg5-Atg16L complex (function as an E3-like enzyme). The PE-conjugated LC3, named LC3-II, is localized to the inner and outer membranes of the isolation membrane and is essential for membrane biogenesis and closure of the isolation membrane. The activated ULK1 complex regulates class III PI3K complex and the multimembrane spanning protein Atg9L at pre-autophagosomal structure/phagophore-assembly site (PAS) close to the endoplasmic reticulum (ER), which is involved in the formation of the omegasome. PI3P-binding WIPIs, Atg12–Atg5–Atg16L1 complex, and LC3–PE conjugate play important roles in the elongation and closure of the isolation membrane/phagophore. ER indicates endoplasmic reticulum; PI3P, phosphatidylinositol 3-phosphate.The molecular underpinnings of autophagosome formation were uncovered mainly in yeast Saccharomyces cerevisiae. To date, genetic studies of S. cerevisiae have identified >30 autophagy-related (ATG) genes, 18 of which are core ATG genes that are essential for autophagosome formation.3 Importantly, core ATG genes are well conserved in mammals, where the functions of the encoded proteins markedly overlap with the corresponding proteins in yeast, although a few mammal-specific proteins have been identified. Atg proteins are categorized into several subclasses, but they function sequentially and cooperatively to regulate autophagosome formation (Figure 1).4 The ubiquitin-like modifiers Atg12 and LC3 (mammalian Atg8 homolog) are activated by the E1-like enzyme Atg7 and transferred to 2 different E2-like enzymes: Atg10 and Atg3, respectively. Whereas Atg12 forms an isopeptide bond with Atg5, LC3 forms an amide bond with phosphatidylethanolamine (PE) in a reaction dependent on the Atg12-Atg5 conjugation. Atg16L forms a high-molecular-weight complex with Atg12-Atg5. The Atg12-Atg5-Atg16L complex functions as an E3-like enzyme, determining the site of LC3 lipidation.4 Although the Atg12-Atg5-Atg16L complex is required for elongation of the isolation membrane, the phosphatidylethanolamine-bound LC3 (LC3-II) is thought to be important for membrane biogenesis and closure of the isolation membrane (Figure 1).4In a recent article published in Science, Lee et al1 reported that in primary mouse embryonic fibroblasts, loss of Atg7 abrogated G1-arrest in response to metabolic stress and contact inhibition. Surprisingly, depending on the nature of metabolic stress, Atg7 interacted with p53 directly, and this complex then bound to the promoter region of Cdkn1a, a cyclin-dependent kinase inhibitor (Figure 2). These events resulted in modulation of Cdkn1a expression and inhibition of entry into the S-phase. Paradoxically, the same group noticed the upregulation of p53-dependent proapoptotic genes, such as Puma, Bax, and Noxa, in primary Atg7−/− mouse embryonic fibroblasts. Autophagy-deficient mouse embryonic fibroblasts showed increased production of reactive oxygen species and DNA damage, which activated the DNA damage sensor, ataxia teleangiecstasia mutated kinase. Subsequently, the mediator molecule Chk2 phosphorylated Ser20 of p53, followed by induction of a series of proapoptotic genes (Figure 2). As expected, changes in the expression of these genes were completely blocked by the additional loss of Chk2. The phosphorylation of p53 and enhanced cell death observed in Atg7−/− mouse embryonic fibroblasts were restored by simultaneous depletion of Chk2. Furthermore, the neonatal lethality of Atg7-knockout mice was rescued, at least in part, in Atg7 Chk2-double knockout mice.Download figureDownload PowerPointFigure 2. Schematic model of cell cycle and cell death in Atg7-deficient mouse embryonic fibroblasts (MEFs) under metabolic stress conditions. In response to metabolic stress, the p53-Atg7 complex binds to the promoter region of Cdkn1a to induce its expression, leading to G1-arrest. Lack of Atg7 abrogates the induction of Cdkn1a and exit from cell division cycle. Meanwhile, accumulation of DNA damage through impaired mitochondria homeostasis in Atg7-knockout mice activates DNA damage sensor, ATM kinase. Subsequently, Chk2 phosphorylates Ser20 of p53, followed by induction of a series of proapoptotic genes. Imbalance between cell division and cell death could lead to hematopoietic cell death, neurodegeneration, and tumorigenesis. ROS indicates reactive oxygen species.Finkel et al1 have suggested that the interaction of Atg7 with p53 in response to metabolic stress and contact inhibition is a rate-limiting step for the induction of Cdkn1a, followed by G1-arrest (Figure 2). What are the factors that enhance the Atg7-p53 interaction? Evidence suggests that acetylation plays an important role in autophagy.5,6 Previous studies indicated that Sirt1 deacetylates several Atg proteins, including Atg7, which is indispensable for starvation-induced autophagy,7 and conversely that p300 acetyltransferase directly interacts with and acetylates Atg7 to inhibit autophagy.8 Beyond autophagic regulation, deacetylation of Atg7 might promote the interaction with p53 to induce Cdkn1a gene expression. Because the structures of both Atg7 and tetramerization domain of p53 have been analyzed,9,10 determination of the structure of the Atg7-TET domain complex is feasible. Structural analysis should enhance our understanding of the role of Atg7 in cell cycle regulation.What is the physiological importance of the p53-Atg7 pathway in the regulation of cell cycle arrest? Exit from cell division cycle (ie, upregulation of Cdkn1a) seems to be dependent on Atg7 but not other Atg proteins, such as Atg5 and Beclin 1, indicating an additive function of Atg7 beyond autophagy. Hence, loss of Atg7 in mice should be associated with worse phenotypes than other Atg-knockout mice. Nevertheless, to date, we have not observed any profound phenotypes of Atg7-knockout mice compared with those of Atg5- or Atg3-knockout mice.11–13 These mutant mice are born in accordance with Mendelian inheritance ratios and survive but have lower amino acid levels in their sera and tissues and die within the first day of life. Further in vivo add-back experiment of mutant Atg7, which is defective in interaction with p53, but capable of induction of autophagy, will be critical for understanding the physiological significance of the p53-Atg7 pathway.Overcoming neonatal death in autophagy-deficient mice by additional loss of Chk2 is surprising because the autophagy-deficient mice have multiple systemic defects, including neurological abnormalities and impaired trophic dynamics.11,14 Finkel et al1 have shown the induction of proapoptotic pathways only in livers of Atg7−/− neonate mice. The livers of neonate mice contain a large number of hematopoietic stem cells and related cells, such as erythroid cells. Recent studies have shed light on the importance of autophagy in mitochondrial homeostasis (mitophagy)15 and indicated that defective mitophagy in hematopoietic cells is directly linked to rapid cell death. In fact, impaired autophagy in hematopoietic stem cells, T cells, and B cells causes acute cell death because of the accumulation of damaged mitochondria, followed by production of reactive oxygen species.16,17 Therefore, suppression of cell death in these cells by additional loss of Chk2 is plausible. What about other tissues? The authors asserted that there was neurodegeneration in Atg7 Chk2-double knockout mice. However, partial rescue of neurological defect in autophagy-deficient mice is expected because loss of Chk2 restores the suckling disorder in Atg7−/− mice (the double-mutant mouse cannot survive >1 day unless it overcomes this defect).Imbalance between cell growth and death contributes to tumorigenesis. Mice heterozygous for Beclin 1 mutation, systemically mosaic for Atg5 deficiency, or lacking Atg7 specifically in liver tissue develop liver tumors, probably because of dysregulation of signal transduction pathways, as well as impaired organelle quality control.18–21 The growth of liver adenoma in mice with liver-specific knockouts of Atg7 is markedly suppressed when p62 is also knocked out, because marked accumulation of p62, due to loss of autophagy, leads to dysregulation of nuclear factor-κB signaling, activation of apoptosis, and responses to environmental stress.22,23 However, loss of p62 does not suppress hepatocarcinogenesis itself. The autophagy-related p53 pathways might be engaged in tumorigenesis (Figure 2). Further studies are needed to determine the state of tumorigenesis in Atg7 Chk2-double deficient mice.The report by Finkel et al1 helps our understanding of the molecular mechanism by which impaired autophagy and Atg-related proteins are involved in apoptosis and cell cycle arrest. However, pathophysiological significance of the regulation remains unclear as described in this commentary. With the recent development of sophisticated research tools, such as Cre-mediated conditional knockout techniques, it has become clear that loss of autophagy is associated with various life-threatening diseases, such as neurodegeneration, cardiomyopathy, liver injury, glomerulosclerosis, myopathy, and cancer.2 Further studies are needed to clarify the pathological role of proapoptotic genes in autophagy-deficient tissues in these diseases (Figure 2).Sources of FundingM. Komatsu is supported by the Funding Program for Next Generation World-Leading Researchers (Japan).DisclosuresNone.FootnotesThe opinions in this Commentary are not necessarily those of the editors or of the American Heart Association.Commentaries serve as a forum in which experts highlight and discuss articles (published here and elsewhere) that the editors of Circulation Research feel are of particular significance to cardiovascular medicine.Commentaries are edited by Aruni Bhatnagar & Ali J. Marian.Correspondence to Masaaki Komatsu, Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan. E-mail [email protected]References1. Lee IH, Kawai Y, Fergusson MM, Rovira II, Bishop AJ, Motoyama N, Cao L, Finkel T. Atg7 modulates p53 activity to regulate cell cycle and survival during metabolic stress.Science. 2012; 336:225–228.CrossrefMedlineGoogle Scholar2. Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues.Cell. 2011; 147:728–741.CrossrefMedlineGoogle Scholar3. Nakatogawa H, Suzuki K, Kamada Y, Ohsumi Y. Dynamics and diversity in autophagy mechanisms: lessons from yeast.Nat Rev Mol Cell Biol. 2009; 10:458–467.CrossrefMedlineGoogle Scholar4. Mizushima N, Yoshimori T, Ohsumi Y. The role of Atg proteins in autophagosome formation.Annu Rev Cell Dev Biol. 2011; 27:107–132.CrossrefMedlineGoogle Scholar5. Yi C, Ma M, Ran L, et al. Function and molecular mechanism of acetylation in autophagy regulation.Science. 2012; 336:474–477.CrossrefMedlineGoogle Scholar6. Lin SY, Li TY, Liu Q, et al. GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy.Science. 2012; 336:477–481.CrossrefMedlineGoogle Scholar7. Lee IH, Cao L, Mostoslavsky R, Lombard DB, Liu J, Bruns NE, Tsokos M, Alt FW, Finkel T. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy.Proc Natl Acad Sci USA. 2008; 105:3374–3379.CrossrefMedlineGoogle Scholar8. Lee IH, Finkel T. Regulation of autophagy by the p300 acetyltransferase.J Biol Chem. 2009; 284:6322–6328.CrossrefMedlineGoogle Scholar9. Cho Y, Gorina S, Jeffrey PD, Pavletich NP. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations.Science. 1994; 265:346–355.CrossrefMedlineGoogle Scholar10. Noda NN, Satoo K, Fujioka Y, Kumeta H, Ogura K, Nakatogawa H, Ohsumi Y, Inagaki F. Structural basis of Atg8 activation by a homodimeric E1, Atg7.Mol Cell. 2011; 44:462–475.CrossrefMedlineGoogle Scholar11. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N. The role of autophagy during the early neonatal starvation period.Nature. 2004; 432:1032–1036.CrossrefMedlineGoogle Scholar12. Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, Tanida I, Ezaki J, Mizushima N, Ohsumi Y, Uchiyama Y, Kominami E, Tanaka K, Chiba T. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice.J Cell Biol. 2005; 169:425–434.CrossrefMedlineGoogle Scholar13. Sou YS, Waguri S, Iwata J, Ueno T, Fujimura T, Hara T, Sawada N, Yamada A, Mizushima N, Uchiyama Y, Kominami E, Tanaka K, Komatsu M. The Atg8 conjugation system is indispensable for proper development of autophagic isolation membranes in mice.Mol Biol Cell. 2008; 19:4762–4775.CrossrefMedlineGoogle Scholar14. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, Mizushima N. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice.Nature. 2006; 441:885–889.CrossrefMedlineGoogle Scholar15. Youle RJ, Narendra DP. Mechanisms of mitophagy.Nat Rev Mol Cell Biol. 2011; 12:9–14.CrossrefMedlineGoogle Scholar16. Pua HH, Dzhagalov I, Chuck M, Mizushima N, He YW. A critical role for the autophagy gene Atg5 in T cell survival and proliferation.J Exp Med. 2007; 204:25–31.CrossrefMedlineGoogle Scholar17. Mortensen M, Soilleux EJ, Djordjevic G, Tripp R, Lutteropp M, Sadighi-Akha E, Stranks AJ, Glanville J, Knight S, Jacobsen SE, Kranc KR, Simon AK. The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance.J Exp Med. 2011; 208:455–467.CrossrefMedlineGoogle Scholar18. Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor.Proc Natl Acad Sci USA. 2003; 100:15077–15082.CrossrefMedlineGoogle Scholar19. Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, Rosen J, Eskelinen EL, Mizushima N, Ohsumi Y, Cattoretti G, Levine B. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene.J Clin Invest. 2003; 112:1809–1820.CrossrefMedlineGoogle Scholar20. Inami Y, Waguri S, Sakamoto A, Kouno T, Nakada K, Hino O, Watanabe S, Ando J, Iwadate M, Yamamoto M, Lee MS, Tanaka K, Komatsu M. Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells.J Cell Biol. 2011; 193:275–284.CrossrefMedlineGoogle Scholar21. Takamura A, Komatsu M, Hara T, Sakamoto A, Kishi C, Waguri S, Eishi Y, Hino O, Tanaka K, Mizushima N. Autophagy-deficient mice develop multiple liver tumors.Genes Dev. 2011; 25:795–800.CrossrefMedlineGoogle Scholar22. Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY, Bray K, Reddy A, Bhanot G, Gelinas C, Dipaola RS, Karantza-Wadsworth V, White E. Autophagy suppresses tumorigenesis through elimination of p62.Cell. 2009; 137:1062–1075.CrossrefMedlineGoogle Scholar23. Komatsu M, Kurokawa H, Waguri S, et al. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1.Nat Cell Biol. 2010; 12:213–223.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Wang T, Feng X, Li L, Luo J, Liu X, Zheng J, Fan X, Liu Y, Xu X, Zhou G and Chen L (2022) Effects of quercetin on tenderness, apoptotic and autophagy signalling in chickens during post-mortem ageing, Food Chemistry, 10.1016/j.foodchem.2022.132409, 383, (132409), Online publication date: 1-Jul-2022. ZHANG L, YU Y, XIA X, MA Y, CHEN X, NI Z and WANG H (2016)(2016) Transcription factor E2-2 inhibits the proliferation of endothelial progenitor cells by suppressing autophagy, International Journal of Molecular Medicine, 10.3892/ijmm.2016.2521, 37:5, (1254-1262), Online publication date: 1-May-2016. Lindqvist L, Simon A and Baehrecke E (2015) Current questions and possible controversies in autophagy, Cell Death Discovery, 10.1038/cddiscovery.2015.36, 1:1, Online publication date: 1-Dec-2015. Bestebroer J, V'kovski P, Mauthe M and Reggiori F (2013) Hidden Behind Autophagy: The Unconventional Roles of ATG Proteins, Traffic, 10.1111/tra.12091, 14:10, (1029-1041), Online publication date: 1-Oct-2013. September 28, 2012Vol 111, Issue 8 Advertisement Article InformationMetrics © 2012 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.112.280768PMID: 23023507 Originally publishedSeptember 28, 2012 PDF download Advertisement" @default.
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• W2146122012 title "Impaired G1-Arrest, Autophagy, and Apoptosis in <i>Atg7</i> -Knockout Mice" @default.
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