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Mol Cancer Res:YAP1蛋白触发脑膜瘤细胞增殖

来源:生物谷 2012-06-14 19:44

近日,约翰霍普金斯大学的研究人员发表论文称:他们已经发现脑膜瘤生长的重要的细胞机制之一。

在脑膜瘤细胞中,Baia研究激活的蛋白质YAP1,这是由Hippo调控的蛋白。没有Hippo,YAP1会移动到细胞核,并激活触发肿瘤细胞增殖的基因。

近年来,已发现Hippo信号通路在其他类型的癌细胞生长中发挥了作用,但该研究是第一次证实该通路与脑膜瘤有关。YAP1也与其他癌症有关联包括肺癌和卵巢的恶性肿瘤,NF2突变存在于其他不太常见的脑癌类型中。

在他们的研究中,研究人员收集了70例脑膜瘤组织样本,发现所有样品的原子核中都表达YAP1,并且不与肿瘤的发展历程相关,这意味着它似乎在脑膜瘤的早期阶段就存在。在实验室研究中,研究人员敲除细胞核YAP1后发现,肿瘤细胞增会受到抑制。但当YAP1表达增多时,细胞生长和迁移也更快。

研究人员正在开发针对这一靶基因的新的治疗方法。这项研究由Leonard和Phyllis Attman基金会捐款支持。(生物谷:Bioon.com)

Yes-Associated Protein 1 Is Activated and Functions as an Oncogene in Meningiomas

G. S. Baia, O. L. Caballero, B. A. Orr, A. Lal, J. S. Y. Ho, C. Cowdrey, T. Tihan, C. Mawrin, G. J. Riggins.

The Hippo signaling pathway is functionally conserved in Drosophila melanogaster and mammals and its proposed function is to control tissue homeostasis by regulating cell proliferation and apoptosis. The core components are comprised of a kinase cascade that culminates with the phosphorylation and inhibition of Yes-associated protein 1 (YAP1). Phospho-YAP1 is retained in the cytoplasm. In the absence of Hippo signaling, YAP1 translocates to the nucleus, associates with co-activators TEAD1-4 and functions as a transcriptional factor promoting the expression of key target genes. Components of the Hippo pathway are mutated in human cancers and deregulation of this pathway plays a role in tumorigenesis. Loss of the NF2 tumor suppressor gene is the most common genetic alteration in meningiomas and the NF2 gene product, Merlin acts upstream of the Hippo pathway. Here we show that primary meningioma tumors have high nuclear expression of YAP1. In meningioma cells, Merlin expression is associated with phosphorylation of YAP1. Using a siRNA transient knockdown of YAP1 in NF2 mutant meningioma cells we show that suppression of YAP1 impaired cell proliferation and migration. Conversely, YAP1 overexpression led to a strong augment of cell proliferation and anchorage-independent growth, and restriction of cisplatin-induced apoptosis. In addition, expression of YAP1 in nontransformed arachnoidal cells led to the development of tumors in nude mice. Together, these findings suggest that in meningiomas deregulation of the Hippo pathway is largely observed in primary tumors and that YAP1 functions as an oncogene promoting meningioma tumorigenesis.

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