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91.
Komatsu M Waguri S Chiba T Murata S Iwata J Tanida I Ueno T Koike M Uchiyama Y Kominami E Tanaka K 《Nature》2006,441(7095):880-884
Protein quality-control, especially the removal of proteins with aberrant structures, has an important role in maintaining the homeostasis of non-dividing neural cells. In addition to the ubiquitin-proteasome system, emerging evidence points to the importance of autophagy--the bulk protein degradation pathway involved in starvation-induced and constitutive protein turnover--in the protein quality-control process. However, little is known about the precise roles of autophagy in neurons. Here we report that loss of Atg7 (autophagy-related 7), a gene essential for autophagy, leads to neurodegeneration. We found that mice lacking Atg7 specifically in the central nervous system showed behavioural defects, including abnormal limb-clasping reflexes and a reduction in coordinated movement, and died within 28 weeks of birth. Atg7 deficiency caused massive neuronal loss in the cerebral and cerebellar cortices. Notably, polyubiquitinated proteins accumulated in autophagy-deficient neurons as inclusion bodies, which increased in size and number with ageing. There was, however, no obvious alteration in proteasome function. Our results indicate that autophagy is essential for the survival of neural cells, and that impairment of autophagy is implicated in the pathogenesis of neurodegenerative disorders involving ubiquitin-containing inclusion bodies. 相似文献
92.
H. Kobayashi K. Hasegawa M. Tanaka M. Kikuno 《Cellular and molecular life sciences : CMLS》1978,34(6):750-751
Summary The subcellular distribution of cholinesterase (ChE) was studied in the gastrocnemius muscle of rats after strong or weak nerve crushing. The ChE activities of muscle were decreased to a greater extent by strong crushing than by weak crushing. In particular, the ChE activity of the fraction containing sarcoplasmic reticulum was most greatly decreased. These results suggest that the change in the ChE activity of the microsomal fraction most finely reflects the strength of nerve crushing.Acknowledgments. This study was accomplished in Central Research Laboratories, Sankyo Co. Ltd. The authors wish to thank Prof. Tsuneyuki Nakazawa, Department of Neuropsychiatry, School of Medicine, Fujita-Gakuen University, and Dr Yutaka Sakai for their valuable advice and support, Sr Jean M. Michalec for her critical comments, and Miss Hamako Katano, Mr Naoji Mikuni and Miss Yoshie Ishii for their skillful technical assistance. 相似文献
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96.
Y Murakami S Matsufuji T Kameji S Hayashi K Igarashi T Tamura K Tanaka A Ichihara 《Nature》1992,360(6404):597-599
Ornithine decarboxylase (ODC), a key enzyme in polyamine biosynthesis, is the most rapidly turned over mammalian enzyme. We have shown that its degradation is accelerated by ODC antizyme, an inhibitory protein induced by polyamines. This is a new type of enzyme regulation and may be a model for selective protein degradation. Here we report the identification of the protease responsible for ODC degradation. Using a cell-free degradation system, we demonstrate that immunodepletion of proteasomes from cell extracts causes almost complete loss of ATP- and antizyme-dependent degradation of ODC. In addition, purified 26S proteasome complex, but not the 20S proteasome, catalyses ODC degradation in the absence of ubiquitin. These results strongly suggest that the 26S proteasome, widely viewed as specific for ubiquitin-conjugated proteins, is the main enzyme responsible for ODC degradation. The 26S proteasome may therefore have a second role in ubiquitin-independent proteolysis. 相似文献
97.
T Aoyagi T Wada F Kojima M Nagai S Harada T Takeuchi K Isse M Ogura M Hamamoto K Tanaka 《Experientia》1992,48(7):656-659
Previously we reported that there is a kallikrein deficiency in the cerebral tissue of patients with Alzheimer-type dementia. The present study was performed to investigate protease changes in the serum of these patients. The results showed that the kallikrein activity was normal, but that the activities of plasmin and urokinase were significantly low. The present findings indicate a derangement in the clotting and fibrinolytic systems in Alzheimer patients. 相似文献
98.
Suppression of tumorigenicity in human colon carcinoma cells by introduction of normal chromosome 5 or 18. 总被引:18,自引:0,他引:18
Development of colon carcinomas can be associated with allelic deletions on several chromosomes, including 5q and 18q. The APC gene on 5q and the DCC gene on 18q have been identified as potential tumour suppressor genes, whose suppression contributes to colon carcinogenesis. To investigate the role of genes in these deleted regions, we have now introduced a single normal human chromosome into a human colon carcinoma cell line, COKFu, through microcell hybridization. Several clones of hybrid cells containing normal chromosome 5, and others containing normal chromosome 18, were obtained. The morphology of the hybrid cells was markedly altered: the hybrids with chromosome 5 exhibited a closely packed polygonal morphology, and the hybrid cells with chromosome 18 were flattened. The cloning efficiency of the hybrid cells in soft agar was reduced from 0.46 to 0% of that of the parental carcinoma cells, and the tumorigenicity of these hybrid cells in athymic nude mice was completely suppressed. The growth properties of the hybrid cells with chromosome 11 were not substantially changed. These results strongly suggest that the genes on normal chromosome 5 and 18 function as tumour suppressors in colon carcinogenesis. 相似文献
99.
Zusammenfassung Versuche mit14C-markiertem Carcinogen MNNG ergaben an Ratten nach einmaliger Verabreichung der Substanz eine vorwiegend über die Niere erfolgende Elimination. Die Metabolite von MNNG in Verknüpfung mit verschiedenen Stoffwechselstufen und ihre Verteilung im Gewebe wurden näher verfolgt. 相似文献
100.
Diltiazem prevents the damage to cultured aortic smooth muscle cells induced by hyperlipidemic serum
Diltiazem, a calcium antagonist, significantly reduced the increased 45Ca uptake and the number of dead cells in cultured aortic smooth muscle cells induced by hyperlipidemic serum. 相似文献