Disease relevance of Autophagy

• Here, we show that Runx1 is required to sustain muscle by preventing denervated myofibers from undergoing myofibrillar disorganization and autophagy, structural defects found in a variety of congenital myopathies [1].
• The beclin 1 autophagy gene is monoallelically deleted in 40-75% of cases of human sporadic breast, ovarian, and prostate cancer [2].
• Furthermore, PKR and eIF2alpha Ser-51-dependent autophagy is antagonized by the herpes simplex virus neurovirulence protein, ICP34 [3].
• Previously, we showed that rapamycin, an autophagy inducer, enhances mutant huntingtin fragment clearance and attenuated toxicity [4].
• This study adds a new concept to characterize the pathways by which ceramide acts to induce nonapoptotic autophagic cell death in malignant gliomas [5].

Psychiatry related information on Autophagy

• X-linked vacuolar myopathies can be divided into two forms: one that is associated with cardiomyopathy and mental retardation (XVCM-MR) and a second form, termed X-linked myopathy with excessive autophagy (XMEA), that spares cardiac muscle and has no central nervous system involvement [6].

High impact information on Autophagy

• Here we show that plant BECLIN 1, an ortholog of the yeast and mammalian autophagy gene ATG6/VPS30/beclin 1, functions to restrict HR PCD to infection sites [7].
• Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy [8].
• The anti-apoptotic protein, Bcl-2, interacts with the evolutionarily conserved autophagy protein, Beclin 1 [8].
• In this issue of Cell, new evidence indicates that autophagy is used to for survival when intracellular nutrients are limited by growth factor deprivation (Lum et al., 2005) [9].
• Sequestration of mTOR impairs its kinase activity and induces autophagy, a key clearance pathway for mutant huntingtin fragments [10].

Chemical compound and disease context of Autophagy

• Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells [11].
• Induction of autophagic cell death in malignant glioma cells by arsenic trioxide [12].
• Dopamine induces autophagic cell death and alpha-synuclein increase in human neuroblastoma SH-SY5Y cells [13].
• Nano neodymium oxide induces massive vacuolization and autophagic cell death in non-small cell lung cancer NCI-H460 cells [14].
• The first molecular evidence that autophagy relates rimmed vacuole formation in chloroquine myopathy [15].

Biological context of Autophagy

• Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes [16].
• Furthermore, beclin 1 heterozygous disruption results in increased cellular proliferation and reduced autophagy in vivo [2].
• p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death [17].
• AUT2 and AUT7, two novel genes essential for autophagocytosis in the yeast Saccharomyces cerevisiae were isolated [18].
• We also find that dephosphorylation of Apg13p, a signal transduction event that correlates with the onset of autophagy, is also independent of new protein synthesis [19].

Anatomical context of Autophagy

• Runx1 prevents wasting, myofibrillar disorganization, and autophagy of skeletal muscle [1].
• Changes in biliary excretion of lysosomal enzymes accompanying chloroquine and glucagon administration were associated with morphologic evidence of autophagy as assessed by electron microscopy and by increased fragility of hepatic lysosomes as assessed by latency of N-acetyl-beta-glucosaminidase [20].
• Double membrane-bounded vacuoles were formed in the peripheral cytoplasm during sucrose starvation and were eventually expelled into the central vacuole, which increased in volume and squeezed the thin layer of cytoplasm spared by autophagy [21].
• Here we demonstrate that the rat microtubule-associated protein 1 light chain 3 (LC3), a homologue of Apg8p essential for autophagy in yeast, is associated to the autophagosome membranes after processing [22].
• These results strongly suggest that the supply of mitochondria with respiratory substrates, and not the decrease of sucrose and hexose phosphates, controls the induction of autophagy in plant cells starved in carbohydrates [21].

Associations of Autophagy with chemical compounds

• This non-apoptotic death of double knockout cells was suppressed by inhibitors of autophagy, including 3-methyl adenine, was dependent on autophagic proteins APG5 and Beclin 1 (capable of binding to Bcl-2/Bcl-x(L)), and was also modulated by Bcl-x(L) [16].
• The formation of AVi was prevented by 3-methyladenine, a potent inhibitor of autophagy [23].
• We tested these possibilities by assaying the effects of cycloheximide and specific mutations on the induction of autophagy [19].
• No recycling back to the hexose phosphates was observed, and cells were rapidly depleted in sugars and hexose phosphates, without any sign of autophagy [21].
• Lithium induces autophagy by inhibiting inositol monophosphatase [24].

Gene context of Autophagy

• Apg8/Aut7 is an essential factor for autophagy in yeast [25].
• CONCLUSIONS: The progressive disappearance of acinar cells in Spink3(-/-) mice was due to autophagic cell death and impaired regeneration [26].
• Cvt9 oligomers peripherally associate with a novel, perivacuolar membrane compartment and interact with Apg1, a Ser/Thr kinase essential for both the Cvt pathway and autophagy [27].
• Here, we characterize a requirement for Vps34 in constitutive autophagy by the cytoplasm-to-vacuole targeting (Cvt) pathway [28].
• Apg9p/Cvt7p is the first characterized integral membrane protein required for Cvt and autophagy transport [29].

Analytical, diagnostic and therapeutic context of Autophagy

• Molecular dissection of autophagy: two ubiquitin-like systems [30].
• The by nutrient deprivation-increased autophagocytosis was confirmed by transmission electron microscopy and uptake of the lysosomotropic weak base acridine orange within the intracellular acidic vacuolar apparatus [31].
• Analysis by cDNA microarray, RT-PCR, and Western blot showed that cell death members of Bcl-2 family, Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 (BNIP3) and its homologue BNIP3-like (BNIP3L), were upregulated in As(2)O(3)-induced autophagic cell death [32].
• The process of autophagy was studied in Tritrichomonas foetus under serum deprivation, drug treatment (hydroxyurea, zinc sulfate), and also in normal conditions using routine electron microscopy, freeze-fracture, freeze-substitution, and enzyme cytochemistry [33].
• The influence of insulin treatment (group 1) and allogenic islet transplantation (group 2) on renal cellular autophagy were evaluated in adult Lewis rats in the early phase of streptozotocin-induced diabetes mellitus--a condition in which autophagy is inhibited and renal mass is increased [34].

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