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31.
Shc (Src homology and collagen homology) proteins are considered prototypical signalling adaptors in mammalian cells. Consisting of four unique members, ShcA, B, C and D, and multiple splice isoforms, the family is represented in nearly every cell type in the body, where it engages in an array of fundamental processes to transduce environmental stimuli. Two decades of investigation have begun to illuminate the mechanisms of the flagship ShcA protein, whereas much remains to be learned about the newest discovery, ShcD. It is clear, however, that the distinctive modular architecture of Shc proteins, their promiscuous phosphotyrosine-based interactions with a multitude of membrane receptors, involvement in central cascades including MAPK (mitogen-activated protein kinase) and Akt, and unconventional contributions to oxidative stress and apoptosis all require intricate regulation, and underlie diverse physiological function. From early cardiovascular development and neuronal differentiation to lifespan determination and tumorigenesis, Shc adaptors have proven to be more ubiquitous, versatile and dynamic than their structures alone suggest. 相似文献
32.
M Preukschas C Hagel A Schulte K Weber K Lamszus H Sievert N Pällmann C Bokemeyer J Hauber M Braig S Balabanov 《PloS one》2012,7(8):e43468
Glioblastomas are highly aggressive brain tumors of adults with poor clinical outcome. Despite a broad range of new and more specific treatment strategies, therapy of glioblastomas remains challenging and tumors relapse in all cases. Recent work demonstrated that the posttranslational hypusine modification of the eukaryotic initiation factor 5A (eIF-5A) is a crucial regulator of cell proliferation, differentiation and an important factor in tumor formation, progression and maintenance. Here we report that eIF-5A as well as the hypusine-forming enzymes deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH) are highly overexpressed in glioblastoma patient samples. Importantly, targeting eIF-5A and its hypusine modification with GC7, a specific DHS-inhibitor, showed a strong antiproliferative effect in glioblastoma cell lines in vitro, while normal human astrocytes were not affected. Furthermore, we identified p53 dependent premature senescence, a permanent cell cycle arrest, as the primary outcome in U87-MG cells after treatment with GC7. Strikingly, combined treatment with clinically relevant alkylating agents and GC7 had an additive antiproliferative effect in glioblastoma cell lines. In addition, stable knockdown of eIF-5A and DHS by short hairpin RNA (shRNA) could mimic the antiproliferative effects of GC7. These findings suggest that pharmacological inhibition of eIF-5A may represent a novel concept to treat glioblastomas and may help to substantially improve the clinical course of this tumor entity. 相似文献
33.
Interaction between progesterone and the carbohydrate residues of alpha(1)-acid glycoprotein was followed by fluorescence studies using calcofluor white. The fluorophore interacts with polysaccharides and is commonly used in clinical studies. Binding of progesterone to the protein induces a decrease in the fluorescence intensity of calcofluor white, accompanied by a shift to the short wavelengths of its emission maximum. The dissociation constant of the complex was found equal to 8.62 microM. Interaction between progesterone and free calcofluor in solution induces a low decrease in the fluorescence intensity of the fluorophore without any shift of the emission maximum. These results show that in alpha(1)-acid glycoprotein, the binding site of progesterone is very close to the carbohydrate residues. Fluorescence intensity quenching of free calcofluor in solution with cesium ion gives a bimolecular diffusion constant (k(q)) of 2.23 x 10(9) M(-1) s(-1). This value decreases to 0.19 x 10(9) M(-1) s(-1) when calcofluor white is bound to alpha(1)-acid glycoprotein. Binding of progesterone does not modify the value of k(q) of the cesium. Previous studies have shown that the terminal sialic acid residue is mobile, while the other glycannes are rigid [Albani, J. R.; Sillen, A.; Coddeville, B.; Plancke, Y. D.; Engelborghs, Y. Carbohydr. Res. 1999, 322, 87-94]. Red-edge excitation spectra and Perrin plot experiments performed on sialylated and asialylated alpha(1)-acid glycoprotein show that binding of progesterone to alpha(1)-acid glycoprotein does not modify the local dynamics of the carbohydrate residues of the protein. 相似文献
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35.
T. D. Nguyen Melanie J. Smith Peter Hersey 《Cancer immunology, immunotherapy : CII》1997,43(6):345-354
Determinants of T cell responses to tumor cells remain largely unknown. In the present study we have used long-term cultures
of human melanoma cells and autologous peripheral blood lymphocytes to examine the influence of cytokines with T cell growth
activity on the phenotype and cytotoxic and proliferative response of T cells to melanoma. It was found that addition of interleukin-4
(IL-4) inhibited the response of CD8+ T cells and promoted the response of the CD4 subset. IL-2 or IL-7 was effective in increasing melanoma-specific cytotoxic
T lymphocyte (CTL) activity in cultures where CD8 T cells were predominant, whereas IL-4 followed by IL-2 was most effective
in cultures where CD4 T cells predominated. IL-10 or IL-12 inhibited proliferation and CTL activity against melanoma in long-term
cultures. The effects of IL-12 were reproduced in long-term cultures of T cells stimulated with mAb against CD3 and were shown
to depend on prior exposure of T cells to IL-12 before IL-2. As yet unidentified factors, such as co-factor expression on
melanoma, appear to be as important as exogenous cytokines in determining the nature of T cell responses to melanoma. These
results suggest that analysis of responses in long-term culture may assist in defining the role of key cytokines and other
determinants of immune responses to melanoma.
Received: 4 June 1996 / Accepted: 12 November 1996 相似文献
36.
37.
The antiviral and antitumor activity in vitro of normal, stimulated, vaccinia virus “immune”, and activated peritoneal macrophages were compared. Activated (pyran or corynebacteria induced) PEC exhibited both antitumor and antiviral activity. Stimulated (thioglyocollate) and vaccinia virus “immune” PEC inhibited virus growth but did not possess antitumor activity. Normal (unstimulated) PEC were relatively ineffective in either activity. The antiviral activity was nonspecific, being expressed against herpes simplex and EMC viruses in addition to vaccinia. Although a possible role for interferon was suggested by the lack of activity of mouse PEC on vaccinia virus growth in heterologous FLK cells, definitive proof was not obtained. The activity was most pronounced against multiple cycles of viral infection initiated at a low multiplicity of infection. Single cycle virus growth was not affected, suggesting that the major inhibition was on subsequent cycles of virus growth. 相似文献
38.
39.
The pattern of RNA synthesis of intracellular Trypanosoma cruzi amastigotes, immediately following infection of Lesch-Nyhan human fibroblasts, was studied by autoradiography. Amastigote RNA synthesis, determined by [3H]guanine incorporation, was not detected until 2 h after infection. At 8 h postinfection more than 90% of intracellular amastigotes were labeled. It was verified that extracellular trypomastigotes also synthesized RNA. Therefore it was concluded that, if RNA is required for trypomastigote-to-amastigote transformation, this nucleic acid is already present in the trypomastigotes before infection of the vertebrate cell. It is probable that the RNA synthesized by amastigotes during the prereplicative lag period (the period between initial infection and the onset of DNA synthesis) is required for intracellular growth and reproduction. 相似文献
40.
Thomas M Davis Melanie E Shields Qian Zhang Denise Tombolato-Terzić Jeffrey L Bennetzen Ana C Pontaroli Hao Wang Qin Yao Phillip SanMiguel Kevin M Folta 《BMC plant biology》2010,10(1):81