Hedgehog pathway regulation by the LKB1/SIK signaling cascade.

描述(申请人提供)：Hedgehog(HH)信号转导通路调节胚胎发育中的细胞迁移、增殖和分化等细胞过程。毫不奇怪，HH信号的失调与肿瘤的发生有关；调节通路组件的突变与髓母细胞瘤和基底细胞癌有关，这两种肿瘤分别是最常见的脑癌和皮肤癌。此外，在其他癌症中也观察到HH途径活性上调，包括前列腺癌、乳腺癌和肺癌。最近的一项假说表明，其他信号通路中的致癌事件可能导致HH信号的不正确激活，并支持癌症的进展。如果这是真的，这一假设表明，HH途径可能为许多癌症的治疗提供了一个治疗机会。最近，我们的实验室发现了信号通路的三个组成部分，它们的缺失会导致HH通路激活的增加。这三种蛋白：LKB1、SIK1和SIK2，是LKB1/SIK信号级联的成员。LKB1本身是一种肿瘤抑制基因，它的缺失会导致遗传病Peutz-Jegher综合征。这可能代表了一种调节HH信号的新机制，也可能为远端途径中的致癌事件如何导致HH信号调节失调提供了一个模型。换句话说，这是一个癌症中HH信号普遍上调的模型。有两个目的：第一，了解LKB1/SIK信号通路中哪些成员参与了HH通路的调控。第二，研究LKB1/SIK信号引起HH通路激活的机制。为了实现这些目标，我将研究丢失、过表达和突变对细胞培养中LKB1/SIK途径成分的影响。我还将研究这些扰动在斑马鱼中的生理后果，以了解这些观察到的体内相关性。然后，我将通过对单个HH蛋白缺失的细胞系中LKB1/SIK丢失进行建模，上位论地映射LKB1/SIK途径扰动相对于已知HH途径成分的影响。通过这种方式，我希望系统地确定所涉及的LKB1/SIK途径组件的身份，以及它们在HH途径中的伙伴的身份。公共卫生相关性：这项提案调查了一项新的观察，将两条与癌症相关的生物学途径联系在一起。通过了解这一联系，我们希望确定一些癌症进展的一般模式，这可能会为疾病的治疗提供新的策略。

DESCRIPTION (provided by applicant): The Hedgehog (Hh) signal transduction pathway regulates cellular processes such as cell migration, proliferation and differentiation in embryo development. Unsurprisingly, dysregulation of Hh signaling is implicated in oncogenesis; mutations to regulatory pathway components are linked to medulloblastoma and basal cell carcinoma, the most common brain and skin cancers, respectively. Furthermore, upregulated Hh pathway activity has been observed in other cancers, including prostate, breast and lung. A recent hypothesis suggests that oncogenic events in other signaling pathways may result in improper activation of Hh signaling, and support cancer progression. If true, this hypothesis suggests that the Hh pathway may present a therapeutic opportunity in the treatment of many cancers. Recently, our lab identified three components of a signaling pathway whose loss resulted in increased Hh pathway activation. These three proteins: LKB1, SIK1 and SIK2, are members of the LKB1/SIK signaling cascade. LKB1 itself is a tumor suppressor gene, whose loss results in the genetic disease Peutz-Jegher's syndrome. This potentially represents a novel mechanism for regulation of Hh signaling, and may also suggest a model for how an oncogenic event in a distal pathway could result in dysregulation of Hh signaling. In other words, a model for the general upregulation of Hh signaling in cancer. There are two aims: first, to understand which members of the LKB1/SIK signaling pathway participate in Hh pathway regulation. Second, to characterize the mechanism by which LKB1/SIK signals cause Hh pathway activation. To accomplish these aims I will study the effects of loss, overexpression and mutation on LKB1/SIK pathway components in cell culture. I will also examine the physiological consequences of these perturbations in zebrafish, to understand the in vivo relevance of these observations. I will then epistatically map the effects of LKB1/SIK pathway perturbation relative to known Hh pathway components, by modeling LKB1/SIK loss in cell lines with deletions for individual Hh proteins. In this way I hope to systematically determine the identities of the LKB1/SIK pathway components involved, and the identities of their partners in the Hh pathway. Public Health Relevance: This proposal investigates a novel observation linking two cancer-relevant biological pathways. In understanding this connection, we hope to identify a general pattern in the progression of some cancers which may suggest novel strategies for the treatment of disease.