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Inhibition of Shc/Grb2 protein-protein interaction suppresses growth of B104-1-1 tumors xenografted in nude mice

机译:抑制Shc / Grb2蛋白相互作用抑制裸鼠异种移植的B104-1-1肿瘤的生长

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Actinomycin D was revealed as an inhibitor of Shc/Grb2 interaction in cell lines from our recent study. She and Grb2 proteins are important molecules in Ras signaling pathways leading to cellular differentiation and proliferation, which require dramatic morphological changes. It was detected by transmission electron microscopy that actinomycin D induced significant changes in cellular ultrastructures of B104-1-1 cells and confirmed that the changes were due to inhibition of Shc/Grb2 interaction by actinomycin D rather than its inhibitory effect on transcription. Because actinomycin D was dispersed mainly in cytoplasm and She peptide (synthetic 13 amino acid tyrosine phosphorylated polypeptide) successfully displaced actinomycin D binding to its cellular targets while the other polypeptide from PDGF receptor could not. We examined the effect of actinomycin D on growth of B104-1-1 tumor xenografted in nude mice. Tumor growth was inhibited in vivo after treatment with this inhibitor. Efficacy was correlated with a reduction in the levels of Shc/Grb2 binding in excised tumors. These results suggest that actinomycin D inhibited Shc/Grb2 interaction in B104-1-1 tumor xenografted in nude mice. (c) 2005 Elsevier Inc. All rights reserved.
机译:最近的研究表明,放线菌素D是细胞系Shc / Grb2相互作用的抑制剂。 She和Grb2蛋白是Ras信号传导途径中的重要分子,导致细胞分化和增殖,这需要剧烈的形态变化。通过透射电子显微镜检测到,放线菌素D诱导了B104-1-1细胞的细胞超微结构的显着变化,并证实该变化是由于放线菌素D抑制了Shc / Grb2相互作用,而不是其对转录的抑制作用。因为放线菌素D主要分散在细胞质中,而She肽(合成的13个氨基酸的酪氨酸磷酸化多肽)成功取代了放线菌素D与其细胞靶标的结合,而来自PDGF受体的其他多肽则不能。我们检查了放线菌素D对裸鼠异种移植的B104-1-1肿瘤生长的影响。用该抑制剂治疗后,体内肿瘤生长受到抑制。功效与切除的肿瘤中Shc / Grb2结合水平的降低相关。这些结果表明放线菌素D抑制裸鼠异种移植的B104-1-1肿瘤中的Shc / Grb2相互作用。 (c)2005 Elsevier Inc.保留所有权利。

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