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121.
Martin JL Bluhm WF He H Mestril R Dillmann WH 《American journal of physiology. Heart and circulatory physiology》2002,283(1):H85-H91
High levels of alpha B-crystallin are present in the cardiomyocyte, yet little is understood about the function and importance of this protein. Like many other small heat shock proteins, alpha B-crystallin forms large oligomeric complexes whose size can be regulated by posttranslational modifications. The size of these complexes can modify the function of the protein. A naturally occurring COOH-terminal mutant has many detrimental effects in the lens of the eye and altered oligomerization. Therefore, we mutated the two COOH-terminal lysines of alpha B-crystallin to glycines (K174/175G) and adenovirally mounted them to transduce cardiomyocytes. We analyzed the effect of this mutation on oligomerization, microtubular stabilization, and ischemic outcome. A nearly 45% downward shift in complex size was observed with the mutant by native PAGE followed by immunoblotting. The overexpressed protein no longer protected the tubulin cytoskeleton against ischemic stress by confocal analysis. The mutant caused a 30% increase in cytosolic enzyme release with ischemia compared with control, whereas a 33% decrease was associated with wild-type alpha B-crystallin overexpression. We conclude that the COOH terminus of alpha B-crystallin is crucial to its proper function. 相似文献
122.
Pochapsky TC Pochapsky SS Ju T Mo H Al-Mjeni F Maroney MJ 《Nature structural biology》2002,9(12):966-972
Here we report the structure of acireductone dioxygenase (ARD), the first determined for a new family of metalloenzymes. ARD represents a branch point in the methionine salvage pathway leading from methylthioadenosine to methionine and has been shown to catalyze different reactions depending on the type of metal ion bound in the active site. The solution structure of nickel-containing ARD (Ni-ARD) was determined using NMR methods. X-ray absorption spectroscopy, assignment of hyperfine shifted NMR resonances and conserved domain homology were used to model the metal-binding site because of the paramagnetism of the bound Ni2+. Although there is no structure in the Protein Data Bank within 3 A r.m.s deviation of that of Ni-ARD, the enzyme active site is located in a conserved double-stranded b-helix domain. Furthermore, the proposed Ni-ARD active site shows significant post-facto structural homology to the active sites of several metalloenzymes in the cupin superfamily. 相似文献
123.
错配碱基套式PCR-RFLP检测K-ras癌基因第12位密码子点突变,并与一步法PCR-RFLP作比较.结果显示套式PCR-RFLP可检测出500细胞中的一个突变细胞,比一步法PCR-RFLP分析的敏感性提高了100倍.利用该方法检测纤维支气管镜收集的标本中的突变细胞,结果发现9例肺腺癌中有5例发生了K-ras癌基因第12位密码子点突变.提示该方法可行,值得推广应用. 相似文献
124.
Jingru Zhao Xiang Yu Miao Zhu Huaping Kang Jinbiao Ma Min Wu Jianhua Gan Xin Deng Haihua Liang 《PLoS biology》2016,14(4)
Although quorum-sensing (QS) systems are important regulators of virulence gene expression in the opportunistic human pathogen Pseudomonas aeruginosa, their detailed regulatory mechanisms have not been fully characterized. Here, we show that deletion of PA2588 resulted in increased production of pyocyanin and biofilm, as well as enhanced pathogenicity in a mouse model. To gain insights into the function of PA2588, we performed a ChIP-seq assay and identified 28 targets of PA2588, including the intergenic region between PA2588 and pqsH, which encodes the key synthase of Pseudomonas quinolone signal (PQS). Though the C-terminal domain was similar to DNA-binding regions of other AraC family members, structural studies revealed that PA2588 has a novel fold at the N-terminal region (NTR), and its C-terminal HTH (helix-turn-helix) domain is also unique in DNA recognition. We also demonstrated that the adaptor protein ClpS, an essential regulator of ATP-dependent protease ClpAP, directly interacted with PA2588 before delivering CdpR to ClpAP for degradation. We named PA2588 as CdpR (ClpAP-degradation and pathogenicity Regulator). Moreover, deletion of clpP or clpS/clpA promotes bacterial survival in a mouse model of acute pneumonia infection. Taken together, this study uncovered that CdpR is an important QS regulator, which can interact with the ClpAS-P system to regulate the expression of virulence factors and pathogenicity. 相似文献
125.
Genqiang Chen Lin Chen Wei Wang Shiyan Chen Huaping Wang Yen Wei Feng F. Hong 《Microbial biotechnology》2019,12(6):1387-1402
Thirteen agitator configurations were investigated at low speed in stirred-tank reactors (STRs) to determine if improved crude bacterial nanocellulose (BNC) productivity can be achieved from glucose-based media while maintaining high BNC quality using Komagataeibacter xylinus ATCC 23770 as a model organism. A comparison of five single impellers showed the pitched blade (large) was the optimal impeller at 300 rpm. The BNC production was further increased by maintaining the pH at 5.0. Among the single helical ribbon and frame impellers and the combined impellers, the twin pitched blade provided the best results. The combined impellers at 150 rpm performed better than the single impellers, and after optimizing the agitation conditions, the twin pitched blade (large) and helical ribbon impellers performed the best at 100 rpm. The performances of different agitators at low speed during BNC production were related to how efficiently the agitators improved the oxygen mass transfer coefficient. The twin pitched blade (large) was verified as providing the optimum performance by an observed crude BNC production of 1.97 g (L×d)−1 and a BNC crude yield of consumed glucose of 0.41 g g−1, which were 2.25 and 2.37 times higher than the initial values observed using the single impeller respectively. Further characterization indicated that the BNC obtained at 100 rpm from the STR equipped with the optimal agitator maintained high degree of polymerization and crystallinity. 相似文献
126.
Mammary cancer stem cells (MaCSCs) have been identified as a rare population of cells capable of self-renewal to drive mammary tumorigenesis and metastasis. Nevertheless, relatively little is known about the intracellular signaling pathways regulating self-renewal and metastatic activities of MaCSCs in vivo. Using a recently developed breast cancer mouse model with focal adhesion kinase (FAK) deletion in mammary tumor cells (MFCKO-MT mice), here we present evidence suggesting a compensatory function of Pyk2, a FAK-related kinase, in the regulation of MaCSCs and metastasis in these mice. Increased expression of Pyk2 was found selectively in pulmonary metastatic nodules of MFCKO-MT mice, and its inhibition significantly reduced mammary tumor development and metastasis in these mice. Consistent with the idea of metastasis driven by MaCSCs, we detected selective up-regulation of Pyk2 in MaCSCs, but not bulk mammary tumor cells, of primary tumors developed in MFCKO-MT mice. We further showed that inhibition of Pyk2 in FAK-null MaCSCs significantly decreased their tumorsphere formation and migration in vitro as well as self-renewal, tumorigenicity, and metastatic activity in vivo. Last, we identified PI3K/Akt signaling as a major mediator of FAK regulation of MaCSCs as well as a target for the compensatory function of Pyk2 in FAK-null MaCSCs. Together, these results further advance our understanding of FAK and its related tyrosine kinase Pyk2 in regulation of MaCSCs in breast cancer and suggest that pharmaceutically targeting these kinases may hold promise as a novel treatment for the disease by targeting and eradicating MaCSCs. 相似文献
127.
Xin Zhang Mengting Shi Xi Zhao Ennan Bin Yucheng Hu Nan Tang Huaping Dai Chen Wang 《Cell proliferation》2022,55(4)
ObjectivesShort telomeres in alveolar type 2 (AT2) cells have been associated with many lung diseases. The study aimed to investigate the regeneration capacity of AT2 cells with short telomeres by knocking out Tert in mice (G4 Tert −/− ) from the whole to the cellular level.Materials and MethodsThe lung injury model of mice was established by left pneumonectomy (PNX). The proliferation and differentiation of AT2 cells were observed by immunofluorescence staining in vivo and in vitro. The difference of the gene expression between control and G4 Tert −/− group during the regeneration of AT2 cells was compared by RNA sequencing. The expression of tubulin polymerization promoting protein 3 (TPPP3) was reduced by adeno‐associated virus delivery.ResultsThe alveolar regeneration in G4 Tert −/− mice was impaired after PNX‐induced lung injury. The regulation of cytoskeleton remodelling was defective in G4 Tert −/− AT2 cells. The expression of TPPP3 was gradually increased during AT2 cell differentiation. The expression level of TPPP3 was reduced in G4 Tert −/− AT2 cells. Reducing TPPP3 expression in AT2 cells limits the microtubule remodelling and differentiation of AT2 cells.ConclusionShort telomeres in AT2 cells result in the reduced expression level of TPPP3, leading to impaired regeneration capacity of AT2 cells.Short telomeres in alveolar type 2 (AT2) cells have been associated with many lung diseases. The study aimed to investigate the regeneration capacity of AT2 cells with short telomeres by knocking out Tert in mice (G4 Tert −/− ) from the whole to the cellular level. Our findings suggest that short telomeres in AT2 cells result in the reduced expression level of TPPP3, leading to impaired regeneration capacity of AT2 cells. 相似文献
128.
Epithelial tissues facing the external environment are essential to combating microbial infection. In addition to providing a physical barrier, epithelial tissues mount chemical defenses to prevent invasion of internal tissues by pathogens. Here, we describe that the melanization reaction implicated in host defense is activated in the respiratory system, the trachea, of Drosophila. Tracheal melanization can be activated by the presence of microorganisms but is normally blocked by Spn77Ba, a protease inhibitor in the serpin family. Spn77Ba inhibits a protease cascade involving the MP1 and MP2 proteases that activates phenol oxidase, a key enzyme in melanin biosynthesis. Unexpectedly, we found that tracheal melanization resulting from Spn77Ba disruption induces systemic expression of the antifungal peptide Drosomycin via the Toll pathway. Such signaling between local and systemic immune responses could represent an alarm mechanism that prepares the host in case a pathogen breaches epithelial defenses to invade internal tissues. 相似文献
129.
130.
Huaping Fan Xiaofeng Zhao Shaogang Sun Ming Luo Jun-Lin Guan 《The Journal of biological chemistry》2013,288(5):3322-3333
Tyrosine kinases have been shown to play critical roles in cancer development and progression, and their inhibitors hold the potential as effective targeted therapies for breast and other cancers. However, some of these kinases like focal adhesion kinase (FAK) also possess scaffolding functions in intracellular signaling, but such kinase-independent functions of FAK or other kinases have not been examined in cancer directly in vivo. Here, we report that disruption of the function of FAK scaffolding through its Pro-878/881 motif suppressed mammary tumor growth and metastasis in a well characterized murine model of human breast cancer. P878A/P881A mutation in the endogenous FAK gene decreased the expression of markers for epithelial-mesenchymal transition (EMT) and mammary cancer stem cell (MaCSC) activities in tumors derived from mutant mice. This mutation disrupted the function of FAK scaffolding to mediate endophilin A2 phosphorylation at Tyr-315 by Src, leading to the decreased surface expression of MT1-MMP, as observed previously in transformed fibroblasts in vitro. Inhibition of the downstream components of this FAK scaffolding function by Y315F endophilin A2 mutant or MT1-MMP knockdown reduced markers for EMT and MaCSC activities. Conversely, bypass of the scaffolding function using the phosphorylation mimic mutant Y315E endophilin A2 or endophilin A2 knockdown rescued the decreased markers for EMT and MaCSCs as well as surface expression of MT1-MMP in tumor cells harboring the P878A/P881A mutation. Together, these results identify a novel role of FAK scaffolding function in breast cancer, which could serve as a new target in combination with kinase inhibition for more effective treatment strategies. 相似文献