Hedgehog pathway regulation by the LKB1/SIK signaling cascade.

LKB1/SIK 信号级联对 Hedgehog 通路的调节。

基本信息

批准号：
7483471
负责人：
Brian Yi Chuan Feng
金额：
$ 4.68万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7483471
关键词：
Basal cell carcinoma Biological Brain Breast CREB-binding protein CREB1 gene Cell Line Cell Proliferation Cell physiology Cells Chemicals Childhood Brain Neoplasm Cultured Cells Cyclic AMP Disease Distal Embryo Embryonic Development Epigenetic Process Erinaceidae Event Family Fibroblast Growth Factor Fibroblasts GH1 gene Gene Expression Genetic Growth Factor Hereditary Disease Homologous Gene Individual Investigation Knock-out Knockout Mice Laboratories Lead Ligands Link Lung Maintenance Malignant Neoplasms Malignant neoplasm of prostate Maps Modeling Mouse Cell Line Mus Mutation Oncogenic Pathway interactions Pattern Peutz-Jeghers Syndrome Phenotype Phosphotransferases Physiological Play Process Prostate Protein Kinase C Protein Overexpression Proteins Public Health Regulation Regulatory Pathway Relative (related person)Reporting Response Elements Role STK11 gene Signal Pathway Signal Transduction Signaling Protein Skin Skin Cancer Small Interfering RNA Therapeutic Transducers Transgenic Organisms Tumor Suppressor Genes Tumor Suppressor Proteins Up-Regulation Work Zebrafish autocrine cell motility human CREBBP protein in vivo intracellular protein transport medulloblastoma member migration mutant novel novel strategies paracrine protein localization location salt-inducible kinase smoothened signaling pathway therapeutic target transcription factor tumor tumor growth tumor progression tumorigenesis

项目摘要

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.

描述（由申请人提供）：刺猬（HH）信号转导途径调节细胞过程，例如细胞迁移，增殖和胚胎发育中的分化。毫不奇怪，HH信号传导的失调与肿瘤发生有关。调节途径成分的突变与髓母细胞瘤和基底细胞癌（分别是最常见的大脑和皮肤癌）有关。此外，在包括前列腺，乳腺癌和肺在内的其他癌症中也观察到了HH途径的上调。最近的假设表明，其他信号通路中的致癌事件可能导致HH信号的激活不当，并支持癌症的进展。如果是的，则该假设表明HH途径可能会在许多癌症治疗中具有治疗机会。最近，我们的实验室确定了信号通路的三个组成部分，该途径导致HH途径激活增加。这三种蛋白质：LKB1，SIK1和SIK2是LKB1/SIK信号级联的成员。 LKB1本身是肿瘤抑制基因，其损失导致遗传病Peutz-Jegher综合征。这可能代表了调节HH信号传导的新机制，还可能提出一个模型，以了解远端途径中的致癌事件如何导致HH信号传导失调。换句话说，癌症中HH信号传导的一般上调的模型。有两个目的：首先，了解LKB1/SIK信号通路的哪些成员参与HH途径调节。其次，要表征LKB1/SIK信号引起HH途径激活的机制。为了实现这些目标，我将研究损失，过表达和突变对细胞培养中LKB1/SIK途径成分的影响。我还将研究斑马鱼中这些扰动的生理后果，以了解这些观察结果的体内相关性。然后，我将通过对相对于已知HH途径成分的LKB1/SIK途径扰动的影响，通过对单个HH蛋白缺失的细胞系中的LKB1/SIK丢失进行建模。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其在HH途径中的合作伙伴的身份。公共卫生相关性：该提案调查了一个新的观察结果，该观察结果将两种与癌症相关的生物途径联系起来。在理解这一联系时，我们希望确定某些癌症进展的一般模式，这可能暗示了治疗疾病的新策略。