Maintenance of Chromosome Stability by the Hippo Tumor Suppressor Pathway

染色体不稳定(CIN)，广义上定义为数字和结构的持续获得 染色体异常是实体肿瘤的一个标志，已知有助于肿瘤的启动、进展和 旧病复发。因此，CIN的临床预后较差。CIN的发展是一个多步骤的过程：细胞 不仅必须获得导致异常染色体分离的遗传和/或细胞生物学缺陷， 但它们也必须克服非整倍体带来的压力，非整倍体的作用是抑制随后的扩散。 在过去的十年里，大量的努力集中在确定产生 癌细胞中的染色体错误分离。然而，仍然缺乏描述 对染色体数目异常做出反应并限制增殖的机制。因此，如何 细胞适应克服这些生长障碍以成为CIN仍然是一个关键的未解决的问题 癌细胞生物学。我们最近发现，河马肿瘤抑制通路在以下情况下被激活 胞质分裂失败，这限制了由此产生的四倍体细胞的增殖。此外，我们的 初步数据表明，河马信号失活足以促进未转化的CIN 细胞。综上所述，这些发现表明，河马途径可能具有广泛相关的抑制作用 染色体数目异常的细胞的生长。这项提议的目的是澄清 河马通路在感知和响应异常细胞分裂和 非整倍体。其目的是：1)机械地确定河马通路在维持染色体中的作用 稳定性；2)确定河马信号在设定有丝分裂时钟中的作用；3)确定与癌症相关的 河马通路信号的遗传调节。

Chromosome instability (CIN), broadly defined as the persistent acquisition of both numerical and structural chromosome aberrations, is a hallmark of solid tumors that is known to facilitate tumor initiation, progression, and relapse. Consequently, CIN confers poor clinical prognosis. The development of CIN is a multistep process: cells must not only acquire the genetic and/or cell biological defects that induce abnormal chromosome segregation, but they must also overcome the stresses imposed by aneuploidy that act to restrain subsequent proliferation. Over the past decade, significant efforts have focused on identifying the underlying mechanisms that produce chromosome missegregation in cancer cells. However, there remains a paucity of data describing the mechanisms that respond to abnormalities in chromosome number and limit proliferation. Consequently, how cells adapt to overcome these growth barriers in order to become CIN remains a key unresolved question in cancer cell biology. We recently discovered that the Hippo tumor suppressor pathway is activated following cytokinesis failure and that this limits the proliferation of the resulting tetraploid cells. In addition, our preliminary data suggest that inactivation of Hippo signaling is sufficient to promote CIN in non-transformed cells. Together, these findings suggest that the Hippo pathway may have a broadly relevant role in restraining the growth of cells harboring numerical chromosome abnormalities. The goal of this proposal is to elucidate the mechanistic role of the Hippo pathway in both sensing and responding to abnormal cell division and aneuploidy. The aims are: 1) To mechanistically define the role of the Hippo pathway in maintaining chromosome stability; 2) To determine the role of Hippo signaling in setting the mitotic clock; and 3) To identify cancer-relevant genetic regulators of Hippo pathway signaling.