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排序方式: 共有353条查询结果,搜索用时 15 毫秒
271.
272.
Hirschey MD Shimazu T Jing E Grueter CA Collins AM Aouizerat B Stančáková A Goetzman E Lam MM Schwer B Stevens RD Muehlbauer MJ Kakar S Bass NM Kuusisto J Laakso M Alt FW Newgard CB Farese RV Kahn CR Verdin E 《Molecular cell》2011,44(2):177-190
Acetylation is increasingly recognized as an important metabolic regulatory posttranslational protein modification, yet the metabolic consequence of mitochondrial protein hyperacetylation is unknown. We find that high-fat diet (HFD) feeding induces hepatic mitochondrial protein hyperacetylation in mice and downregulation of the major mitochondrial protein deacetylase SIRT3. Mice lacking SIRT3 (SIRT3KO) placed on a HFD show accelerated obesity, insulin resistance, hyperlipidemia, and steatohepatitis compared to wild-type (WT) mice. The lipogenic enzyme stearoyl-CoA desaturase 1 is highly induced in SIRT3KO mice, and its deletion rescues both WT and SIRT3KO mice from HFD-induced hepatic steatosis and insulin resistance. We further identify a single nucleotide polymorphism in the human SIRT3 gene that is suggestive of a genetic association with the metabolic syndrome. This polymorphism encodes a point mutation in the SIRT3 protein, which reduces its overall enzymatic efficiency. Our findings show that loss of SIRT3 and dysregulation of mitochondrial protein acetylation contribute to the metabolic syndrome. 相似文献
273.
Because of discrepancies in the available experimental data, an extensive theoretical investigation of the formation of the
Vilsmeier-Haack (VH) complex has been carried out. The barriers to complex formation calculated using eight different density
functional methods (BLYP, B2-PLYP, B3LYP, B3PW91, MPW1K, M06-2X, and PBE1PBE), MP2, and extrapolation techniques (CBS-QB3,
G3B3) with several basis sets (6 − 31 + G**, 6 − 311++G**, 6 − 311 + (3df,2p), aug-cc-pVDZ, and aug-cc-pVTZ) were compared
with experimental data. For the overall reaction, MP2/aug-cc-pVDZ and M06-2X/6−31 + G(d,p) perform best compared to the CBS
techniques. The results help clarify some open mechanistic questions. 相似文献
274.
Sandhya Noronha Lauren A. C. Alt Taylor E. Scimeca Omran Zarou Justyna Obrzut Brian Zanotti Elizabeth A. Hayward Akhil Pillai Shubha Mathur Joseph Rojas Ribhi Salamah Nalini Chandar Michael J. Fay 《In vitro cellular & developmental biology. Animal》2018,54(1):71-84
Liposarcoma is a malignant soft tissue tumor that originates from adipose tissue and is one of the most frequently diagnosed soft tissue sarcomas in humans. There is great interest in identifying novel chemotherapeutic options for treating liposarcoma based upon molecular alterations in the cancer cells. The Aurora kinases have been identified as promising chemotherapeutic targets based on their altered expression in many human cancers and cellular roles in mitosis and cytokinesis. In this study, we investigated the effects of an Aurora kinase A inhibitor (MK-5108), an Aurora kinase B inhibitor (AZD1152-HQPA), and a pan-Aurora kinase inhibitor (AMG 900) on undifferentiated SW-872 and well-differentiated 93T449 human liposarcoma cells. Treatment of the SW-872 and 93T449 cells with MK-5108 (0–1000 nM), AZD1152-HQPA (0–1000 nM), and AMG 900 (0–1000 nM) for 72 h resulted in a dose-dependent decrease in the total viable cell number. Based upon the EC50 values, the potency of the three Aurora kinase inhibitors in the SW-872 cells was as follows: AMG 900 (EC50 = 3.7 nM) > AZD1152-HQPA (EC50 = 43.4 nM) > MK-5108 (EC50 = 309.0 nM), while the potency in the 93T449 cells was as follows: AMG 900 (EC50 = 6.5 nM) > AZD1152-HQPA (EC50 = 74.5 nM) > MK-5108 (EC50 = 283.6 nM). The percentage of polyploidy after 72 h of drug treatment (0–1000 nM) was determined by propidium iodide staining and flow cytometric analysis. AMG 900 caused a significant increase in polyploidy starting at 25 nM in the SW-872 and 93T449 cells, and AZD1152-HQPA caused a significant increase starting at 100 nM in the SW-872 cells and 250 nM in the 93T449 cells. The Aurora kinase A inhibitor MK-5108 did not significantly increase the percentage of polyploid cells at any of the doses tested in either cell line. The expression of Aurora kinase A and B was evaluated in the SW-872 cells versus differentiated adipocytes and human mesenchymal stem cells by real-time RT-PCR and Western blot analysis. Aurora kinase A and B mRNA expression was significantly increased in the SW-872 cells versus the differentiated adipocytes and human mesenchymal stem cells. Western blot analysis revealed a ~ 48 kDa immunoreactive band for Aurora kinase A that was not present in the differentiated adipocytes or the human mesenchymal stem cells. A ~ 39 kDa immunoreactive band for Aurora kinase B was detected in the SW-872 cells, differentiated adipocytes, and human mesenchymal stem cells. A smaller immunoreactive band for Aurora kinase B was detected in the SW-872 cells but not in the differentiated adipocytes and human mesenchymal stem cells, and this may reflect the expression of a truncated splice variant of Aurora kinase B that has been associated with poor patient prognosis. The 93T449 cells demonstrated decreased expression of Aurora kinase A and B mRNA and protein compared to the SW-872 cells, and also expressed the truncated form of Aurora kinase B. The results of these in vitro studies indicate that Aurora kinase inhibitors should be further investigated as possible chemotherapeutic agents for human liposarcoma. 相似文献
275.
276.
Cdc42 is required for PIP(2)-induced actin polymerization and early development but not for cell viability 总被引:1,自引:0,他引:1
Chen F Ma L Parrini MC Mao X Lopez M Wu C Marks PW Davidson L Kwiatkowski DJ Kirchhausen T Orkin SH Rosen FS Mayer BJ Kirschner MW Alt FW 《Current biology : CB》2000,10(13):758-765
BACKGROUND: Cdc42 and other Rho GTPases are conserved from yeast to humans and are thought to regulate multiple cellular functions by inducing coordinated changes in actin reorganization and by activating signaling pathways leading to specific gene expression. Direct evidence implicating upstream signals and components that regulate Cdc42 activity or for required roles of Cdc42 in activation of downstream protein kinase signaling cascades is minimal, however. Also, whereas genetic analyses have shown that Cdc42 is essential for cell viability in yeast, its potential roles in the growth and development of mammalian cells have not been directly assessed. RESULTS: To elucidate potential functions of Cdc42 mammalian cells, we used gene-targeted mutation to inactivate Cdc42 in mouse embryonic stem (ES) cells and in the mouse germline. Surprisingly, Cdc42-deficient ES cells exhibited normal proliferation and phosphorylation of mitogen- and stress-activated protein kinases. Yet Cdc42 deficiency caused very early embryonic lethality in mice and led to aberrant actin cytoskeletal organization in ES cells. Moreover, extracts from Cdc42-deficient cells failed to support phosphatidylinositol 4,5-bisphosphate (PIP(2))-induced actin polymerization. CONCLUSIONS: Our studies clearly demonstrate that Cdc42 mediates PIP(2)-induced actin assembly, and document a critical and unique role for Cdc42 in this process. Moreover, we conclude that, unexpectedly, Cdc42 is not necessary for viability or proliferation of mammalian early embryonic cells. Cdc42 is, however, absolutely required for early mammalian development. 相似文献
277.
N E Sharpless D O Ferguson R C O'Hagan D H Castrillon C Lee P A Farazi S Alson J Fleming C C Morton K Frank L Chin F W Alt R A DePinho 《Molecular cell》2001,8(6):1187-1196
Although nonhomologous end-joining (NHEJ) deficiency has been shown to accelerate lymphoma formation in mice, its role in suppressing tumors in cells that do not undergo V(D)J recombination is unclear. Utilizing a tumor-prone mouse strain (ink4a/arf(-/-)), we examined the impact of haploinsufficiency of a NHEJ component, DNA ligase IV (Lig4), on murine tumorigenesis. We demonstrate that lig4 heterozygosity promotes the development of soft-tissue sarcomas that possess clonal amplifications, deletions, and translocations. That these genomic alterations are relevant in tumorigenesis is supported by the finding of frequent mdm2 amplification, a known oncogene in human sarcoma. Together, these findings support the view that loss of a single lig4 allele results in NHEJ activity being sufficiently reduced to engender chromosomal aberrations that drive non-lymphoid tumorigenesis. 相似文献
278.
Esra Üçüncü Tunca Tolga T. Ölmez Alper D. Özkan Ahmet Altındağ Evren Tunca Turgay Tekinay 《International journal of phytoremediation》2016,18(8):785-793
Following the rapid uptake of contaminants in the first few hours of exposure, plants typically attempt to cope with the toxic burden by releasing part of the sorbed material back into the environment. The present study investigates the general trends in the release profiles of different metal(loid)s in the aquatic macrophyte Lemna minor and details the correlations that exist between the release of metal(loid) species. Water samples with distinct contamination profiles were taken from Nilüfer River (Bursa, Turkey), Yeniça?a Lake (Bolu, Turkey), and Bey?ehir Lake (Konya, Turkey) and used for release studies; 36 samples were tested in total. Accumulation and release profiles were monitored over five days for 11 metals and a metalloid (208Pb, 111Cd, 52Cr,53Cr,60Ni,63Cu,65Cu,75As,55Mn, 137Ba, 27Al, 57Fe, 66Zn,68Zn) and correlation, cluster and principal component analyses were employed to determine the factors that affect the release of these elements. Release profiles of the tested metal(loid)s were largely observed to be distinct; however, strong correlations have been observed between certain metal pairs (Cr/Ni, Cr/Cu, Zn/Ni) and principal component analysis was able to separate the metal(loid)s into three well-resolved groups based on their release. 相似文献
279.
280.