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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Wild-type p53 controls cell motility and invasion by dual regulation of MET expression
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Wild-type p53 controls cell motility and invasion by dual regulation of MET expression

机译：野生型p53通过MET表达的双重调节控制细胞运动和侵袭

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摘要

Recent observations suggest that p53 mutations are responsible not only for growth of primary tumors but also for their dissemination. However, mechanisms involved in pS3-mediated control of cell motility and invasion remain poorly understood. By using the primary ovarian surface epithelium cell culture, we show that conditional inactivation of p53 or expression of its mutant forms results in overexpression of MET receptor tyrosine kinase, a crucial regulator of invasive growth. At the same time, cells' acquire increased MET-dependent motility and invasion. Wild-type p53 negatively regulates MET expression by two mechanisms: (i) trans-activation of MET-targeting miR-34, and (ii) inhibition of SP1 binding to MET promoter. Both mechanisms are not functional in p53 absence, but mutant p53 proteins retain partial MET promoter suppression. Accordingly, MET overexpression, cell motility, and invasion are particularly high in p53-null cells. These results identify MET as a critical effector of p53 and suggest that inhibition of MET may be an effective antimetastatic approach to treat cancers with p53 mutations. These results also show that the extent of advanced cancer traits, such as invasion, may be determined by alterations in individual components of p53/MET regulatory network.
机译：最近的观察表明，p53突变不仅负责原发性肿瘤的生长，而且还负责其扩散。但是，涉及pS3介导的细胞运动和侵袭控制的机制仍然知之甚少。通过使用原发性卵巢表面上皮细胞培养，我们显示p53的条件失活或其突变体形式的表达导致MET受体酪氨酸激酶（侵袭性生长的关键调节剂）的过表达。同时，细胞获得增加的MET依赖性运动和侵袭。野生型p53通过两种机制负调节MET表达：（i）靶向MET的miR-34的反式激活，以及（ii）SP1与MET启动子结合的抑制。在缺少p53的情况下，这两种机制均不起作用，但是突变的p53蛋白保留了部分MET启动子抑制。因此，在p53无效的细胞中，MET过表达，细胞运动性和侵袭特别高。这些结果确定了MET是p53的关键效应子，并表明抑制MET可能是治疗具有p53突变的癌症的有效抗转移方法。这些结果还表明，晚期癌症特征（如侵袭）的程度可能由p53 / MET调节网络各个组成部分的改变决定。

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    Chang-ll Hwang; Andres Matoso; David C. Corney; Andrea Flesken-Nikitin; Stefanie Koerner; Wei Wang; Carla Boccaccio; Snorri S. Thorgeirsson; Paolo M. Comoglio; Heiko Hermeking; Alexander Yu. Nikitin;

  • 作者单位

    Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853;

    Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853;

    Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853;

    Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853;

    Experimental and Molecular Pathology, Institute of Pathology, The Ludwig-Maximilians University, D-80337 Munich, Germany;

    Microarray Core Facility, Cornell University, Ithaca, NY 14853;

    Division of Molecular Oncology, Institute for Cancer Research and Treatment, University of Torino Medical School, 10060 Candiolo, Italy;

    National Cancer Institute, National Institutes of Health, Laboratory of Experimental Carcinogenesis, Center for Cancer Research, Bethesda, MD 20892;

    Division of Molecular Oncology, Institute for Cancer Research and Treatment, University of Torino Medical School, 10060 Candiolo, Italy;

    Experimental and Molecular Pathology, Institute of Pathology, The Ludwig-Maximilians University, D-80337 Munich, Germany;

    Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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