Crosstalk between Desmogleins and Canonical Hedgehog Signaling

桥粒糖蛋白和典型 Hedgehog 信号之间的串扰

基本信息

批准号：
8699728
负责人：
Donna Brennan-Crispi
金额：
$ 4.27万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8699728
关键词：
1-Phosphatidylinositol 3-Kinase Accounting Agonist Alleles Asses Basal Cell Basal cell carcinoma Biological Assay Bromodeoxyuridine Cadherins Carcinoma Caspase Cell Adhesion Cell Adhesion Molecules Cell Line Cell Proliferation Cell Survival Cell physiology Cell-Cell Adhesion Chemicals Classification Congenital Abnormality Cyclic AMP-Dependent Protein Kinases Data Development Diagnosis Disease Disease Progression Epidermal Growth Factor Receptor Epidermis Epithelial Erinaceidae Genetic Transcription Goals Growth Human Immigration Incidence LacZ Genes Luciferases Malignant Epithelial Cell Malignant Neoplasms Mediating Metalloproteases Molecular Target Monitor Mus Mutation Oncogenic Pathway interactions Predisposition Process Proteins Proteolytic Processing Proto-Oncogene Proteins c-akt RNA Interference Regulation Relative (related person)Reporter Research Role Sampling Signal Pathway Signal Transduction Signaling Molecule Skin Skin Cancer Skin Neoplasms Squamous cell carcinoma Testing Tissue Microarray Transcriptional Activation Transgenic Mice Tumor Tissue United States Work cancer therapy cancer type carcinogenesis cell growth design desmoglein desmoglein 2 in vitro activity in vivo inhibitor/antagonist insight keratinocyte mouse model novel overexpression programs receptor smoothened signaling pathway therapeutic target transcription factor translational approach translational study tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Skin cancer is the most common human cancer and BCCs and SCCs make up a vast majority of these malignancies. In the case of BCCs a causal role of canonical Hedgehog (Hh) pathway activation has been well-established, and recent evidence further supports a role for canonical Hedgehog signaling in SCCs as well. Hh signaling is a key developmental pathway involved in cells proliferation and survival through downstream activation of Gli transcription factors. The Hh pathway can be regulated by other signaling cascades; including EGFR, Wnt/-catenin, IGFR and TGF. Key signaling molecules have been shown to be required for Gli activation including Gi proteins, PI3K and AKT; while PKA and GSK3¿ promote partial Gli degradation. Interestingly, BCCs and SCCs, among other cancer types, are also characterized by increased expression of the desmosomal cadherin Desmoglein 2 (Dsg2). Furthermore, overexpression of DSg2 in transgenic mice results in epidermal hyperproliferation, enhanced cell survival, and renders keratinocytes more susceptible to chemically induced carcinogenesis. Thus the goal of this project is to elucidate a potential crosstalk between Dsg2 and canonical Hh signaling. Using a transgenic mouse model overexpressing Dsg2, our preliminary results indicate a significant correlation between Dsg2 expression and Hh target gene transcription. Since these mice are more susceptible to chemically induced carcinogenesis, the potential for Dsg2 to mediate changes in cell growth and survival could be in part mediated by enhanced Gli activity. Gli-luciferase assays demonstrate that the expression of Dsg2 can enhance Gli activity in vitro. Finally, knockdown of Dsg2 in an SCC cell line results in decreased Gli expression. Taken together, these results suggest a role for Dsg2 as a positive regulator of canonical Hh signaling. The studies proposed here are designed to elucidate the mechanism by which Dsg2 enhances Gli activity, by both determining at what level of Hh signaling Dsg2 is acting and if Dsg2 processing by metalloproteases and/or caspases is necessary for this regulation. In vivo work using mice that overexpress Dsg2 and which are prone to Hh signaling activation (Ptc1+/lacZ) will provide insights into the consequences of simultaneous deregulation of both pathways in the skin. Finally, a translational study looking at the expression of Dsg2 and Hh proteins in human BCC and SCC samples will allow for the correlation of the deregulation of both pathways with tumor type and classification. Together these mechanistic studies will offer a clearer understanding of how canonical Hh signaling can be regulated by cell adhesion proteins; the ramifications of said deregulation with regards to cell proliferation, survival and oncogenic potential; and provide potential targets for novel cancer therapies.

描述（由适用提供）：皮肤癌是最常见的人类癌症，而BCC和SCC占此类恶性肿瘤的绝大多数。在BCC的情况下，已建立了典型的刺猬（HH）途径的因果作用，并且最近的证据进一步支持了SCC中规范刺猬信号的作用。 HH信号传导是通过GLI转录因子的下游激活细胞增殖和存活涉及的关键发育途径。 HH途径可以通过其他信号级联反应来调节；包括EGFR，WNT/-CATENIN，IGFR和TGF。已证明关键信号分子是GLI激活所必需的，包括GI蛋白，PI3K和AKT。而pka和gsk3。促进部分GLI降解。有趣的是，BCC和SCC以及其他癌症类型的特征在于脱染色体钙粘着蛋白脱木质2（DSG2）的表达增加。此外，DSG2在转基因小鼠中的过表达会导致表皮过度增殖，增强的细胞存活以及使角质形成细胞更容易受到化学诱导的致癌作用的影响。该项目的目标是阐明DSG2和规范HH信号之间的潜在串扰。使用过表达DSG2的转基因小鼠模型，我们的初步结果表明DSG2表达与HH靶基因转录之间存在显着相关性。由于这些小鼠更容易受到化学诱导的癌变的影响，因此DSG2介导细胞生长和生存的变化的潜力可能部分是由GLI活性增强所介导的。 Gli-核酶阿萨斯表明DSG2的表达可以在体外增强GLI活性。最后，在SCC细胞系中DSG2的敲低导致GLI表达降低。综上所述，这些结果表明DSG2作为规范HH信号的正调节剂的作用。此处提出的研究旨在通过确定在哪种HH信号DSG2的作用以及金属蛋白酶和/或caspases处理的HH信号dsg2的含量是在哪种水平上通过确定dsg2增强GLI活性的机制。使用过表达DSG2并且容易出现HH信号激活（PTC1+/LACZ）的小鼠的体内工作，将为您提供对皮肤两种途径的简单放松管制的后果的见解。最后，一项翻译研究，研究人类BCC和SCC样品中DSG2和HH蛋白的表达，将允许两种途径与肿瘤类型和分类的放松管制的相关性。这些机械研究将共同对如何通过细胞粘合剂蛋白来调节典型的HH信号传导有更清晰的了解。在细胞增殖，生存和致癌潜力方面，上述放松管制的影响；并为新型癌症疗法提供潜在的靶标。