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首页> 外文期刊>Cell cycle >p27 deficiency is associated with migration defects in PDGF-expressing gliomas in vivo.
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p27 deficiency is associated with migration defects in PDGF-expressing gliomas in vivo.

机译：p27缺乏与表达PDGF的神经胶质瘤在体内的迁移缺陷有关。

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p27(Kip1) is a cyclin dependent kinase inhibitor that functions as a tumor suppressor in a variety of different cancers. While p27 has a well established role in regulating the cell cycle, it has also been shown to regulate cellular migration by influencing the activation state of the small GTP ase RhoA. We recently demonstrated that loss of p27 enhances tumor progression and leads to a dramatic decrease in survival in PDGF-induced oligodendrogliomas. Here we show that p27 deficient PDGF-expressing glial cells contained elevated levels of Rho-GTP and were less migratory than wild type cells. Migration defects in p27 deficient cells were rescued by either Rho kinase inhibition or expression of p27 or CK(-), a mutant of p27 that cannot bind cyclins/cdks. The RCAS/tv-a retroviral system was used to specifically induce PDGF-expressing gliomas in mice. Many of the p27 deficient mice died earlier than wild type mice and displayed hydrocephalus which was associated with periventricular tumors that failed to invade the normal brain parenchyma. Invasion failure was reversed by co-expression of PDGF with either the GAP domain of p190(RhoGAP), a negative regulator of Rho, or p27, or CK(-). These results suggest that p27 mediated regulation of the Rho pathway is cell cycle independent and demonstrate for the first time a migration defect in cancer cells that is associated with p27 deficiency in vivo in a mouse tumor model.
机译：p27（Kip1）是细胞周期蛋白依赖性激酶抑制剂，在多种不同的癌症中起着抑癌作用。尽管p27在调节细胞周期中具有公认的作用，但它也已显示出通过影响小GTP酶RhoA的激活状态来调节细胞迁移。我们最近证明，p27的缺失会增强肿瘤的进展，并导致PDGF诱导的少突胶质细胞瘤的存活率急剧下降。在这里，我们显示p27缺陷PDGF表达神经胶质细胞包含升高水平的Rho-GTP，并且比野生型细胞迁移少。通过Rho激酶抑制或p27或CK（-）（不能结合细胞周期蛋白/ cdks的p27突变体）的表达来挽救p27缺陷细胞中的迁移缺陷。使用RCAS / tv-a逆转录病毒系统特异性诱导小鼠中表达PDGF的神经胶质瘤。许多p27缺陷小鼠死于野生型小鼠，并表现出脑积水，这与未能侵袭正常脑实质的脑室周围肿瘤有关。 PDGF与p190（RhoGAP），Rho的负调节子或p27或CK（-）的GAP域共表达可逆转侵袭失败。这些结果表明p27介导的Rho途径的调节是细胞周期独立的，并首次证明在小鼠肿瘤模型中癌细胞中的迁移缺陷与体内p27缺乏有关。

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