共查询到20条相似文献,搜索用时 15 毫秒
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Helin Vakifahmetoglu-Norberg Minsu Kim Hong-guang Xia Marcin P. Iwanicki Dimitry Ofengeim Jonathan L. Coloff Lifeng Pan Tan A. Ince Guido Kroemer Joan S. Brugge Junying Yuan 《Genes & development》2013,27(15):1718-1730
Missense mutations in the gene TP53, which encodes p53, one of the most important tumor suppressors, are common in human cancers. Accumulated mutant p53 proteins are known to actively contribute to tumor development and metastasis. Thus, promoting the removal of mutant p53 proteins in cancer cells may have therapeutic significance. Here we investigated the mechanisms that govern the turnover of mutant p53 in nonproliferating tumor cells using a combination of pharmacological and genetic approaches. We show that suppression of macroautophagy by multiple means promotes the degradation of mutant p53 through chaperone-mediated autophagy in a lysosome-dependent fashion. In addition, depletion of mutant p53 expression due to macroautophagy inhibition sensitizes the death of dormant cancer cells under nonproliferating conditions. Taken together, our results delineate a novel strategy for killing tumor cells that depend on mutant p53 expression by the activation of chaperone-mediated autophagy and potential pharmacological means to reduce the levels of accumulated mutant p53 without the restriction of mutant p53 conformation in quiescent tumor cells. 相似文献
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Benham AM 《Antioxidants & redox signaling》2005,7(5-6):835-838
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Kon M Kiffin R Koga H Chapochnick J Macian F Varticovski L Cuervo AM 《Science translational medicine》2011,3(109):109ra117
The cellular process of autophagy (literally "self-eating") is important for maintaining the homeostasis and bioenergetics of mammalian cells. Two of the best-studied mechanisms of autophagy are macroautophagy and chaperone-mediated autophagy (CMA). Changes in macroautophagy activity have been described in cancer cells and in solid tumors, and inhibition of macroautophagy promotes tumorigenesis. Because normal cells respond to inhibition of macroautophagy by up-regulation of the CMA pathway, we aimed to characterize the CMA status in different cancer cells and to determine the contribution of changes in CMA to tumorigenesis. Here, we show consistent up-regulation of CMA in different types of cancer cells regardless of the status of macroautophagy. We also demonstrate an increase in CMA components in human cancers of different types and origins. CMA is required for cancer cell proliferation in vitro because it contributes to the maintenance of the metabolic alterations characteristic of malignant cells. Using human lung cancer xenografts in mice, we confirmed the CMA dependence of cancer cells in vivo. Inhibition of CMA delays xenograft tumor growth, reduces the number of cancer metastases, and induces regression of existing human lung cancer xenografts in mice. The fact that similar manipulations of CMA also reduce tumor growth of two different melanoma cell lines suggests that targeting this autophagic pathway may have broad antitumorigenic potential. 相似文献
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Protein disulfide isomerase (PDI) catalyzes the formation of native disulfide pairings in secretory proteins. The ability of PDI to act as a disulfide isomerase makes it an essential enzyme in eukaryotes. PDI also fulfills other important roles. Recent studies have emphasized the importance of PDI as an oxidant in the endoplasmic reticulum. Intriguing questions remain regarding how PDI is able to catalyze both isomerization and oxidation in vivo. Studies of PDI and its homologues have led to the development of small-molecule folding catalysts that are able to accelerate disulfide isomerization in vitro and in vivo. PDI will continue to provide both an inspiration for the design of such artificial foldases and a benchmark with which to gauge the success of those designs. Here, we review current understanding of the chemistry and biology of PDI, its homologues, and small molecules that mimic its catalytic activity. 相似文献
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Disulfide bonds are required for the stability and function of many proteins. A large number of thiol-disulfide oxidoreductases, belonging to the thioredoxin superfamily, catalyze protein disulfide bond formation in all living cells, from bacteria to humans. The protein disulfide isomerase (PDI) is the eukaryotic factor that catalyzes oxidative protein folding in the endoplasmic reticulum; by contrast, in prokaryotes, a family of disulfide bond (Dsb) proteins have an equivalent outcome in the bacterial periplasm. Recently the results from genome analysis suggested an important role for disulfide bonds in the structural stabilization of intracellular proteins from thermophiles. A specific protein disulfide oxidoreductase (PDO) has a key role in intracellular disulfide shuffling in thermophiles. Here we focus on the structural and functional characterization of PDO correlated with the multifunctional eukaryotic PDI. In addition, we highlight the chimeric nature of the machinery for oxidative protein folding in thermophiles in comparison with the mesophilic bacterial and eukaryal counterparts. 相似文献
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Acetyl phosphate is a central metabolite involved in a broad range of versatile cellular functions. Recently it was observed that in Escherichia coli the acetyl phosphate pathway is required for efficient ATP-dependent proteolysis. Deletion of the operon coding for acetyl phosphate metabolism (ΔackApta) results in a very low cytoplasmic level of acetyl phosphate and impaired proteolysis. Here we show that the ΔackApta mutation affects additional components of the protein quality control system. Thus, this deletion is accompanied by a decrease in protein refolding and rescue from aggregates. These results indicate the involvement of the acetyl phosphate pathway in chaperone capabilities, in addition to their effect on proteolysis. 相似文献
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F U Hartl 《Seminars in immunology》1991,3(1):5-16
Constitutively expressed heat-shock proteins of the hsp60 and hsp70 families, classified as 'molecular chaperones', have important functions in the folding and intracellular sorting of newly-synthesized proteins. Recent studies of protein translocation across subcellular membranes have shown: (1) Proteins traverse membranes in extended conformations. (2) Cytosolic hsp70 proteins maintain newly-synthesized precursors destined for translocation in a loosely-folded, translocation-competent state. (3) Hsp 70 proteins on the trans-side of the membrane are required for efficient translocation. (4) In the case of mitochondria, the newly-imported polypeptides are transferred to the 'foldase' hsp60, the homologue of the E. coli groEL, which mediates their folding and oligomeric assembly. Hsp70 and hsp60 fulfill these various functions by their abilities, (1) to recognize an unknown structural element(s) which is transiently exposed in unfolded or incompletely folded polypeptides, and (2) to allow cycles of binding and (step-wise) release of the substrate protein catalyzed by ATP-hydrolysis. 相似文献
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Chaperone-mediated cross-priming: a hitchhiker's guide to vesicle transport (review) 总被引:1,自引:0,他引:1
The resident endoplasmic reticulum (ER) chaperone proteins GRP94 (gp96) and calreticulin can activate the immune system to slow or stop the progression of tumors by escorting tumor-derived peptides into the endogenous antigen presentation pathway of antigen presenting cells (APC). Although the phenomenology of cross-priming is well worked out, the mechanism(s) remains unclear. Continuing insights into cellular protein trafficking pathways suggest several means by which chaperones could travel from the extracellular space into the endosome, lysosome or ER of APC. In particular, proteins that cycle between two or more compartments and those that undergo and mediate retrograde flow offer models of how exogenous chaperones might travel in the APC. New insights into how non-chaperone proteins access the APC antigen presentation pathway also suggest several ways this process could occur. 相似文献
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Marx F Salvenmoser W Kaiserer L Graessle S Weiler-Görz R Zadra I Oberparleiter C 《Research in microbiology》2005,156(1):35-46
The Penicillium chrysogenumantifungal protein PAF is secreted into the supernatant after elimination of a preprosequence. PAF is actively internalized into the hyphae of sensitive molds and provokes growth retardation as well as changes in morphology. Thus far, no information is available on the exact mode of action of PAF, nor on the function of its prosequence in protein activity. Therefore, we sought to investigate the effects of secreted PAF as well as of intracellularly retained pro-PAF and mature PAF on the sensitive ascomycete Aspergillus nidulans, and transformed this model organism by expression vectors containing 5'-sequentially truncated paf-coding sequences under the control of the inducible P. chrysogenum-derived xylanase promoter. Indirect immunofluorescence staining revealed the localization of recombinant PAF predominantly in the hyphal tips of the transformant Xylpaf1 which expressed prepro-PAF, whereas the protein was found to be distributed intracellularly within all segments of hyphae of the transformants Xylpaf2 and Xylpaf3 which expressed pro-PAF and mature PAF, respectively. Growth retardation of Xylpaf1 and Xylpaf3 hyphae was detected by proliferation assays and by light microscopy analysis. Using transmission electron microscopy of ultrathin hyphal sections a marked alteration of the mitochondrial ultrastructure in Xylpaf1 was observed and an elevated amount of carbonylated proteins pointed to severe oxidative stress in this strain. The effects induced by secreted recombinant PAF resembled those evoked by native PAF. The results give evidence that properly folded PAF is a prerequisite for its activity. 相似文献
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Ordered nucleic acid in an icosahedral virus was first visualized in the X-ray structure of the Picorna-like plant virus, Bean pod mottle virus (BPMV). Virus particles containing the 3500 nucleotide segment of the BPMV bipartite RNA genome (middle component) had nearly 20% of the genome ordered. Here we report the refined structures of the middle component, bottom component (particles containing the 5800 nucleotide segment of the genome), and top component (empty particles of BPMV capsid protein). The bottom component particles contain ordered RNA in the same location as middle component. Although the ordered RNA density in both nucleoprotein particles is the average of the contents of 60 icosahedral asymmetric units, both nucleoprotein components show that the base density for the first two nucleotides is predominantly purine, while the next five appear to be predominantly pyrimidine. The empty capsid demonstrates that RNA dictates the order of the N-terminal 19 residues of the large subunit because these residues are invisible in the top component. 相似文献
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It is now clear that peptides play a key role in stabilizing the structure of MHC class II molecules. Here, Scheherazade Sadegh-Nasseri and Ron Germain propose that newly synthesized MHC class II, and indeed class I, molecules behave like partially folded proteins, with peptides acting as a surrogate portion of the MHC polypeptide structure that is necessary for completion of conformational maturation. 相似文献