Autophagy and human diseases

Jiang, Peidu; Mizushima, Noboru

doi:10.1038/cr.2013.161

Cited by 693 publications

(507 citation statements)

References 144 publications

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“…[56][57][58][59][60][61][62] The downstream inhibitors of autophagy chloroquine and hydroxychloroquine suppress tumor growth in a laboratory mouse model 63 and have been used in clinical trials of human patients. 56,[59][60][61][62]64 In a clinical trial, the addition of chloroquine has significantly improved median survival of patients with glioblastoma receiving conventional chemotherapy and radiotherapy. 65 However, other studies suggest that chloroquine or hydroxychloroquine is not effective in some types of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia

et al. 2016

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(2016) Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia, Autophagy, 12:6, 1029-1046, DOI: 10.1080/15548627.2016 ABSTRACTAutophagy is an intracellular lysosomal degradation pathway where its primary function is to allow cells to survive under stressful conditions. Autophagy is, however, a double-edge sword that can either promote cell survival or cell death. In cancer, hypoxic regions contribute to poor prognosis due to the ability of cancer cells to adapt to hypoxia in part through autophagy. In contrast, autophagy could contribute to hypoxia induced cell death in cancer cells. In this study, we showed that autophagy increased during hypoxia. At 4 h of hypoxia, autophagy promoted cell survival whereas, after 48 h of hypoxia, autophagy increased cell death. Furthermore, we found that the tyrosine phosphorylation of EGFR (epidermal growth factor receptor) decreased after 16 h in hypoxia. Furthermore, EGFR binding to BECN1 in hypoxia was significantly higher at 4 h compared to 72 h. Knocking down or inhibiting EGFR resulted in an increase in autophagy contributing to increased cell death under hypoxia. In contrast, when EGFR was reactivated by the addition of EGF, the level of autophagy was reduced which led to decreased cell death. Hypoxia led to autophagic degradation of the lipid raft protein CAV1 (caveolin 1) that is known to bind and activate EGFR in a ligand-independent manner during hypoxia. By knocking down CAV1, the amount of EGFR phosphorylation was decreased in hypoxia and amount of autophagy and cell death increased. This indicates that the activation of EGFR plays a critical role in the switch between cell survival and cell death induced by autophagy in hypoxia.

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Section: Discussionmentioning

confidence: 99%

Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia

et al. 2016

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“…25–31 Neuronal functions are highly dependent on protein synthesis and degradation, and a constitutive autophagic flux is fundamental for a number of key neuronal processes. 32–34 Perturbation of the autophagic flux indeed causes neurodevelopmental and neurodegenerative diseases and has been observed, for instance, in Alzheimer disease, Parkinson disease and amyotrophic lateral sclerosis. 33 , 34 Notably, RAB7 regulates autophagosomal maturation controlling the final step of maturation of late autophagic vesicles into autolysosomes, presumably involving fusion with lysosomes.…”

Section: Introductionmentioning

confidence: 99%

Alterations of autophagy in the peripheral neuropathy Charcot-Marie-Tooth type 2B

et al. 2018

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Charcot-Marie-Tooth type 2B (CMT2B) disease is a dominant axonal peripheral neuropathy caused by 5 mutations in the RAB7A gene, a ubiquitously expressed GTPase controlling late endocytic trafficking. In neurons, RAB7A also controls neuronal-specific processes such as NTF (neurotrophin) trafficking and signaling, neurite outgrowth and neuronal migration. Given the involvement of macroautophagy/autophagy in several neurodegenerative diseases and considering that RAB7A is fundamental for autophagosome maturation, we investigated whether CMT2B-causing mutants affect the ability of this gene to regulate autophagy. In HeLa cells, we observed a reduced localization of all CMT2B-causing RAB7A mutants on autophagic compartments. Furthermore, compared to expression of RAB7AWT, expression of these mutants caused a reduced autophagic flux, similar to what happens in cells expressing the dominant negative RAB7AT22N mutant. Consistently, both basal and starvation-induced autophagy were strongly inhibited in skin fibroblasts from a CMT2B patient carrying the RAB7AV162M mutation, suggesting that alteration of the autophagic flux could be responsible for neurodegeneration.

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“…1,2 Because of its fundamental roles in maintaining cellular homeostasis and adapting to various cellular stresses, autophagy is highly relevant for a number of physiologic processes such as embryogenesis, aging and immune response, [3][4][5] and dysfunctions of autophagy are linked with numerous devastating human diseases such as cancer and neurodegenerative diseases. [6][7][8] As the most prevalent subtype of autophagy, macroautophagy (hereafter referred to as autophagy) is characterized by the formation of the double-membrane vesicles termed autophagosomes, which engulf portions of the cytosol and deliver to lysosomes forming the degradative autolysosomes. 9,10 The maturation of autolysosome relies on the tight coordination of autophagic vesicle trafficking.…”

Section: Introductionmentioning

confidence: 99%

Structural basis of FYCO1 and MAP1LC3A interaction reveals a novel binding mode for Atg8-family proteins

Cheng¹,

Wang²,

Gong³

et al. 2016

Autophagy

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FYCO1 (FYVE and coiled-coil domain containing 1) functions as an autophagy adaptor in directly linking autophagosomes with the microtubule-based kinesin motor, and plays an essential role in the microtubule plus end-directed transport of autophagic vesicles. The specific association of FYCO1 with autophagosomes is mediated by its interaction with Atg8-family proteins decorated on the outer surface of autophagosome. However, the mechanistic basis governing the interaction between FYCO1 and Atg8-family proteins is largely unknown. Here, using biochemical and structural analyses, we demonstrated that FYCO1 contains a unique LC3-interacting region (LIR), which discriminately binds to mammalian Atg8 orthologs and preferentially binds to the MAP1LC3A and MAP1LC3B. In addition to uncovering the detailed molecular mechanism underlying the FYCO1 LIR and MAP1LC3A interaction, the determined FYCO1-LIR-MAP1LC3A complex structure also reveals a unique LIR binding mode for Atg8-family proteins, and demonstrates, first, the functional relevance of adjacent sequences C-terminal to the LIR core motif for binding to Atg8-family proteins. Taken together, our findings not only provide new mechanistic insight into FYCO1-mediated transport of autophagosomes, but also expand our understanding of the interaction modes between LIR motifs and Atg8-family proteins in general.

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Autophagy and human diseases

Cited by 693 publications

References 144 publications

Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia

Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia

Alterations of autophagy in the peripheral neuropathy Charcot-Marie-Tooth type 2B

Structural basis of FYCO1 and MAP1LC3A interaction reveals a novel binding mode for Atg8-family proteins

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