Keratins as novel determinants of tumor biology

角蛋白作为肿瘤生物学的新决定因素

• 批准号: 8460109
• 负责人: Pierre Coulombe
• 金额: $ 35.95万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460109
• 关键词: Affect; Architecture; Basal cell carcinoma; Binding; Carcinoma; Cell Proliferation; Cells; Cervix Neoplasms; Code; Cytokeratin filaments; Diagnostic Neoplasm Staging; Disease; Epithelial; Epithelial Cells; Epithelium; Future; Genes; Genetic Transcription; Growth; Human; Human papillomavirus 16; Immune response; Inflammation; Inflammatory Response; Intermediate Filaments; Keratin; Laboratories; Lead; Link; Malignant Neoplasms; Mammary Neoplasms; Maps; Molecular; NF-kappa B; Nature; Oncogene Proteins; Pathway interactions; Physiology; Property; Proteins; Regulation; Relative (related person); Reporting; Risk; Role; Signal Pathway; Single Nucleotide Polymorphism; Skin; Skin Neoplasms; Therapeutic; Time; Tissues; Transgenic Mice; Tumor Biology; Tumor stage; Variant; attenuation; base; cancer diagnosis; chemokine; cytokine; fight against; genome wide association study; in vivo; insight; keratin 5; keratinocyte; mouse model; neoplastic cell; new therapeutic target; novel; outcome forecast; overexpression; pancreatic neoplasm; pre-clinical; tumor; tumor growth; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Type I and type II keratin genes and their proteins undergo a tight regulation in a tissue-specific, differentiation-related, and context-dependent fashion in epithelial cells. Most disease states, including cancer, involve a departure from normal physiology and are invariably accompanied by aberrations in cellular differentiation pathways and keratin regulation. In addition to a ubiquitous and critically important role of structural support, keratin proteins were recently found to impact several key signaling pathways in epithelia. Two recent studies point to a significant modulatory role for two partner keratin proteins, keratin 17 and keratin 5, in basal cell carcinoma and related basaloid skin tumors. This project aims at defining the mechanistic link between these keratins and tumorigenesis in skin, and explore whether it applies to other epithelial tissues. Our specific aims for this project will be as follows. In Aim 1, we will seek to define the molecular mechanism(s) through which keratin 17 enhances the expression of select cytokines and chemokines in Gli2-overexpressing, tumor-prone skin keratinocytes. In Aim 2, we will seek to define the mechanism(s) through which two variants in keratin 5 (Gly138Glu and Asp197Glu) enhance the risk of developing basal cell carcinoma. In Aim 3, we will explore whether keratin 17 impacts the skin and cervical tumors arising in transgenic mice constitutively expressing the E6 and E7 oncoproteins from human papillomavirus 16, and then investigate whether the mechanism(s) underlying keratin-dependent modulation of tumor growth are the same as those uncovered in basal cell carcinoma and basaloid skin tumors. The mechanistic insight acquired about novel determinants of tumor cell architecture and regulation may lead to the identification of new therapeutic targets in the fight against cancer.

描述（由申请人提供）：I型和II型角蛋白基因及其蛋白质在上皮细胞中在组织特异性，与分化有关的和上下文依赖性的方式中经历严格的调节。包括癌症在内的大多数疾病状态都涉及正常生理学，并且总是伴有细胞分化途径和角蛋白调节的畸变。除了无处不在且至关重要的结构支持作用外，最近发现角蛋白蛋白还会影响上皮细胞中的几种关键信号通路。最近的两项研究表明，在基底细胞癌和相关的基底皮肤肿瘤中，两个伴侣角蛋白角蛋白角蛋白17和角蛋白5的调节作用显着。该项目旨在定义这些角蛋白与皮肤中的肿瘤发生之间的机械联系，并探索它是否适用于其他上皮组织。 我们对该项目的具体目标将如下。在AIM 1中，我们将寻求定义角蛋白17的分子机制，从而增强了精选细胞因子和趋化因子在GLI2过表达，易受肿瘤的皮肤角化形成细胞中的表达。在AIM 2中，我们将寻求确定角蛋白5（Gly138GLU和ASP197GLU）中两个变体的机制，从而增强了发展基底细胞癌的风险。在AIM 3中，我们将探讨角蛋白17是否影响转基因小鼠中产生的皮肤和宫颈肿瘤是否形成性地表达来自人乳头瘤病毒16的E6和E7癌蛋白，然后研究肿瘤生长的基本依赖性肿瘤生长的机制是否与那些基本的细胞依赖性细胞can骨相同。关于肿瘤细胞结构和调节的新型决定因素获得的机械洞察力可能会导致鉴定在抗癌战斗中新的治疗靶标。