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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >c-Myc-mediated genomic instability proceeds via a megakaryocytic endomitosis pathway involving Gp1bα
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c-Myc-mediated genomic instability proceeds via a megakaryocytic endomitosis pathway involving Gp1bα

机译：c-Myc介导的基因组不稳定性通过涉及Gp1bα的巨核细胞内吞途径进行

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摘要

Genomic instability (GI) is essential for the initiation and evolution of many cancers and often precedes frank neoplastic conversion. Although GI can occur at several levels, the most conspicuous examples involve gains or losses of entire chromosomes (aneu-ploidy), the antecedent of which may be whole genome duplication (tetraploidy). Through largely undefined mechanisms, the c-Myc oncoprotein and its downstream target, MTMC1, promote tetraploidy and other forms of GI. In myeloid cells, c-Myc and MTMC1 also regulate a common, small subset of c-Myc target genes including GP1Bα, which encodes a subunit of the von Willebrand's factor receptor complex that mediates platelet adhesion and aggregation. Gp1bα also participates in megakaryocyte endomitosis, a form of controlled and precise whole-genome amplification. In this article, we show that both c-Myc and MTMC1 strongly up-regulate Gp1bα concurrent with their promotion of tetraploidy. shRNA-mediated inhibition of Gp1bα prevents tetraploidy by both c-Myc and MTMC1, whereas Gp1bα overexpres-sion alone is sufficient to induce tetraploidy in established and primary cells. Once acquired, tetraploidy persists in most cases examined. Our results indicate that chromosome-level GI, induced by c-Myc overexpression, proceeds by means of the sequential up-regulation of MTMC1 and Gp1bα and further suggest that the pathways leading to megakaryocytic endomitosis and c-Myc-in-duced tetraploidy are mechanistically linked by their reliance on Gp1bα.
机译：基因组不稳定性（GI）对于许多癌症的发生和发展至关重要，并且通常先于坦率的肿瘤转化。尽管GI可以在多个水平上发生，但最明显的例子涉及整个染色体的得失（中性倍性），其前身可能是全基因组复制（四倍性）。通过很大程度上不确定的机制，c-Myc癌蛋白及其下游靶标MTMC1促进四倍体和其他形式的GI。在髓样细胞中，c-Myc和MTMC1还调节c-Myc靶基因的共同小部分，包括GP1Bα，该基因编码介导血小板粘附和聚集的von Willebrand因子受体复合物的一个亚基。 Gp1bα还参与巨核细胞内吞，这是一种受控且精确的全基因组扩增形式。在本文中，我们显示c-Myc和MTMC1都强烈上调Gp1bα，同时促进四倍体。 shRNA介导的Gp1bα抑制作用可阻止c-Myc和MTMC1产生四倍体，而单独的Gp1bα过度表达足以在已建立的和原代细胞中诱导四倍体。一旦获得，在大多数情况下，四倍体仍然存在。我们的结果表明，c-Myc过表达诱导的染色体水平GI通过MTMC1和Gp1bα的顺序上调进行，并进一步表明导致巨核细胞内吞和c-Myc诱导的四倍体的途径是机械的依赖于他们对Gp1bα的联系。

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