CoChat
Sign Up
Cited by 2,105

The DOI matches its Crossref record; 5 of the 5 references it cites were found in a registry or an index.

In Vivo Analysis of Autophagy in Response to Nutrient Starvation Using Transgenic Mice Expressing a Fluorescent Autophagosome Marker

Mizushima, Noboru, Yamamoto, Akitsugu, Matsui, Makoto, Yoshimori, Tamotsu, Ohsumi, Yoshinori·2004·Molecular Biology of the Cell
DOI 10.1091/mbc.e03-09-0704
Open this paper in CoChat — free account

Abstract

Macroautophagy mediates the bulk degradation of cytoplasmic components. It accounts for the degradation of most long-lived proteins: cytoplasmic constituents, including organelles, are sequestered into autophagosomes, which subsequently fuse with lysosomes, where degradation occurs. Although the possible involvement of autophagy in homeostasis, development, cell death, and pathogenesis has been repeatedly pointed out, systematic in vivo analysis has not been performed in mammals, mainly because of a limitation of monitoring methods. To understand where and when autophagy occurs in vivo, we have generated transgenic mice systemically expressing GFP fused to LC3, which is a mammalian homologue of yeast Atg8 (Aut7/Apg8) and serves as a marker protein for autophagosomes. Fluorescence microscopic analyses revealed that autophagy is differently induced by nutrient starvation in most tissues. In some tissues, autophagy even occurs actively without starvation treatments. Our results suggest that the regulation of autophagy is organ dependent and the role of autophagy is not restricted to the starvation response. This transgenic mouse model is a useful tool to study mammalian autophagy.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1091/mbc.e03-09-0704

Cites

5 of 5 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 5 references

Research works printed but not linked: 48

  1. Ariano, M.A., Armstrong, R.B., and Edgerton, V.R. (1973). Hindlimb muscle fiber populations of five mammals. J. Histochem. Cytochem. 21 , 51-55. · DOI
  2. Attaix, D. and Taillandier, D. (1998). The critical role of the ubiquitin-proteasome pathway in muscle wasting in comparison to lysosomal and Ca2+- dependent system . JAI Press Inc., London. · DOI
  3. Bendayan, M., Bruneau, A., and Morisset, J. (1985). Morphometrical and immunocytochemical studies on rat pancreatic acinar cells under control and experimental conditions. Biol. Cell 54 , 227-234. · DOI
  4. Bhat, S.P. (2001). The ocular lens epithelium. Biosci. Rep. 21 , 537-563. · DOI
  5. Blommaart, E.F.C., Luiken, J.J.F.P., and Meijer, A.J. (1997). Autophagic proteolysis: control and specificity. Histochem. J. 29 , 365-385. · DOI
  6. Bowen, I.D. and Lewis, G.H. (1980) Acid phosphatase activity and cell death in mouse thymus. Histochemistry 65 , 173-179. · DOI
  7. Brazil, M.I., Weiss, S., and Stockinger, B. (1997). Excessive degradation of intracellular protein in macrophages prevents presentation in the context of major histocompatibility complex class II molecules. Eur. J. Immunol. 27 , 1506-1514. · DOI
  8. Clarke, P.G. (1990). Developmental cell death: morphological diversity and multiple mechanisms. Anat. Embryol. (Berl.) 181 , 195-213. · DOI · Paper page
  9. Dahlmann, B., Rutschmann, M., and Reinauer, H. (1986). Effect of starvation or treatment with corticosterone on the amount of easily releasable myofilaments in rat skeletal muscles. Biochem. J. 234 , 659-664. · DOI
  10. de Waal, E.J., Vreeling-Sindelarova, H., Schellens, J.P., Houtkooper, J.M., and James, J. (1986). Quantitative changes in the lysosomal vacuolar system of rat hepatocytes during short-term starvation. A morphometric analysis with special reference to macro- and microautophagy. Cell Tissue Res. 243 , 641-648. · DOI
  11. Doelling, J.H., Walker, J.M., Friedman, E.M., Thompson, A.R., and Vierstra, R.D. (2002). The APG8/12-activating enzyme APG7 is required for proper nutrient recycling and senescence in Arabidopsis thaliana. J. Biol. Chem. 277 , 33105-33114. · DOI
  12. Dunn, W.A.J. (1994). Autophagy and related mechanisms of lysosome-mediated protein degradation. Trends Cell Biol. 4 , 139-143. · DOI
  13. Frayn, K.N., and Maycock, P.F. (1979). Regulation of protein metabolism by a physiological concentration of insulin in mouse soleus and extensor digitorum longus muscles. Effects of starvation and scald injury. Biochem. J. 184 , 323-330. · DOI
  14. Hanaoka, H., Noda, T., Shirano, Y., Kato, T., Hayashi, H., Shibata, D., Tabata, S., and Ohsumi, Y. (2002). Leaf senescence and starvation-induced chlorosis are accelerated by the disruption of an Arabidopsis autophagy gene. Plant Physiol. 129 , 1181-1193. · DOI
  15. Hershko, A., and Ciechanover, A. (1998). The ubiquitin system. Annu. Rev. Biochem. 67 , 425-479. · DOI · Paper page
  16. Hochstrasser, M. (1996). Ubiquitin-dependent protein degradation. Annu. Rev. Genet. 30 , 405-439. · DOI
  17. Ichimura, Y. et al. (2000). A ubiquitin-like system mediates protein lipidation. Nature 408 , 488-492. · DOI
  18. Juhasz, G., Csikos, G., Sinka, R., Erdelyi, M., and Sass, M. (2003). The Drosophila homolog of Aut1 is essential for autophagy and development. FEBS Lett. 543 , 154-158. · DOI
  19. Klionsky, D.J. et al. (2003). A unified nomenclature for yeast autophagy-related genes. Dev. Cell 5 , 539-545. · DOI
  20. Klionsky, D.J., and Ohsumi, Y. (1999). Vacuolar import of proteins and organelles from the cytoplasm. Annu. Rev. Cell Dev. Biol. 15 , 1-32. · DOI
  21. Kuma, A., Mizushima, N., Ishihara, N., and Ohsumi, Y. (2002). Formation of the ∼350 kD Apg12-Apg5·Apg16 multimeric complex, mediated by Apg16 oligomerization, is essential for autophagy in yeast. J. Biol. Chem. 277 , 18619-18625. · DOI
  22. Lechler, R., Aichinger, G., and Lightstone, L. (1996). The endogenous pathway of MHC class II antigen presentation. Immunol. Rev. 151 , 51-79. · DOI
  23. Li, J.B., and Goldberg, A.L. (1976). Effects of food deprivation on protein synthesis and degradation in rat skeletal muscles. Am. J. Physiol. Gastrointest. Liver Physiol. 231 , 441-448. · DOI
  24. Lindsten, K., Menendez-Benito, V., Masucci, M.G., and Dantuma, N.P. (2003). A transgenic mouse model of the ubiquitin/proteasome system. Nat. Biotechnol. 21 , 897-902. · DOI
  25. Melendez, A., Talloczy, Z., Seaman, M., Eskelinen, E.L., Hall, D.H., and Levine, B. (2003). Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301 , 1387-1391. · DOI · Paper page
  26. Mizushima, N., Noda, T., and Ohsumi, Y. (1999). Apg16p is required for the function of the Apg12p-Apg5p conjugate in the yeast autophagy pathway. EMBO J. 18 , 3888-3896. · DOI
  27. Mizushima, N., Noda, T., Yoshimori, T., Tanaka, Y., Ishii, T., George, M.D., Klionsky, D.J., Ohsumi, M., and Ohsumi, Y. (1998a). A protein conjugation system essential for autophagy. Nature 395 , 395-398. · DOI
  28. Mizushima, N., Ohsumi, Y., and Yoshimori, T. (2002a). Autophagosome formation in mammalian cells. Cell Struct. Funct. 27 , 421-429. · DOI
  29. Mizushima, N., Sugita, H., Yoshimori, T., and Ohsumi, Y. (1998b). A new protein conjugation system in human. The counterpart of the yeast Apg12p conjugation system essential for autophagy. J. Biol. Chem. 273 , 33889-33892. · DOI
  30. Mizushima, N., Yamamoto, A., Hatano, M., Kobayashi, Y., Kabeya, Y., Suzuki, K., Tokuhisa, T., Ohsumi, Y., and Yoshimori, T. (2001). Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J. Cell Biol. 152 , 657-667. · DOI · Paper page
  31. Mizushima, N., Yoshimori, T., and Ohsumi, Y. (2002b). Mouse Apg10 as an Apg12 conjugating enzyme: analysis by the conjugation-mediated yeast two-hybrid method. FEBS Lett. 532 , 450-454. · DOI
  32. Mortimore, G.E., Hutson, N.J., and Surmacz, C.A. (1983). Quantitative correlation between proteolysis and macro- and microautophagy in mouse hepatocytes during starvation and refeeding. Proc. Natl. Acad. Sci. USA 80 , 2179-2183. · DOI
  33. Mortimore, G.E., and Pösö, A.R. (1987). Intracellular protein catabolism and its control during nutrient deprivation and supply. Annu. Rev. Nutr. 7 , 539-564. · DOI
  34. Nevalainen, T.J., and Janigan, D.T. (1974). Degeneration of mouse pancreatic acinar cells during fasting. Virchows Arch. B Cell Pathol. 15 , 107-118. · DOI
  35. Nishino, I. et al. (2000). Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature 406 , 906-910. · DOI · Paper page
  36. Niwa, H., Yamamura, K., and Miyazaki, J. (1991). Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 108 , 193-199. · DOI
  37. Noda, T., Suzuki, K., and Ohsumi, Y. (2002). Yeast autophagosomes: de novo formation of a membrane structure. Trends Cell Biol. 12 , 231-235. · DOI
  38. Okabe, M., Ikawa, M., Kominami, K., Nakanishi, T., and Nishimune, Y. (1997). `Green mice' as a source of ubiquitous green cells. FEBS Lett. 407 , 313-319. · DOI · Paper page
  39. Otto, G.P., Wu, M.Y., Kazgan, N., Anderson, O.R., and Kessin, R.H. (2003). Macroautophagy is required for multicellular development of the social amoeba Dictyostelium discoideum. J. Biol. Chem. 278 , 17636-17645. · DOI · Paper page
  40. Seglen, P.O., and Bohley, P. (1992). Autophagy and other vacuolar protein degradation mechanisms. Experientia 48 , 158-172. · DOI
  41. Suzuki, K., Kirisako, T., Kamada, Y., Mizushima, N., Noda, T., and Ohsumi, Y. (2001). The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation. EMBO J. 20 , 5971-5981. · DOI
  42. Tanida, I., Tanida-Miyake, E., Komatsu, M., Ueno, T., and Kominami, E. (2002). Human Apg3p/Aut1p homologue is an authentic E2 enzyme for multiple substrates, GATE-16, GABARAP, and MAP-LC3, and facilitates the conjugation of hApg12p to hApg5p. J. Biol. Chem. 277 , 13739-13744. · DOI
  43. Tanida, I., Tanida-Miyake, E., Ueno, T., and Kominami, E. (2001). The human homolog of Saccharomyces cerevisiae Apg7p is a protein-activating enzyme for multiple substrates including human Apg12p, GATE-16, GABARAP, and MAP-LC3. J. Biol. Chem. 276 , 1701-1706. · DOI
  44. Tsukada, M., and Ohsumi, Y. (1993). Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett. 333 , 169-174. · DOI
  45. van Leyen, K., Duvoisin, R.M., Engelhardt, H., and Wiedmann, M. (1998). A function for lipoxygenase in programmed organelle degradation. Nature 395 , 392-395. · DOI
  46. Vary, T.C., and Kimball, S.R. (1992). Sepsis-induced changes in protein synthesis: differential effects on fast- and slow-twitch muscles. Am. J. Physiol. 262 , C1513-C1519. · DOI
  47. Walton, J., and McAvoy, J. (1984). Sequential structural response of lens epithelium to retina-conditioned medium. Exp. Eye Res. 39 , 217-229. · DOI
  48. 10.1091/mbc.11.2.747 · DOI

Cited by

Sorted by citations

Items 101–200 of 204

Metadata

Authors
Mizushima, N., Yamamoto, A., Matsui, M., Yoshimori, T., & Ohsumi, Y.
Affiliations
  • Department of Cell Biology, National Institute for Basic Biology, Okazaki 444-8585, Japan
  • Department of Bio-Science, Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga 526-0829, Japan
  • CREST, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan
Venue
Molecular Biology of the Cell
Publisher
American Society for Cell Biology (ASCB)
Published
2004-03
Volume
15
Issue
3
Pages
1101-1111
ISSN
  • 1059-1524
  • 1939-4586
DOI
10.1091/mbc.e03-09-0704
Cited by
2,105
References
5
Language
en

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review