aPKC function in Hedgehog signaling and basal cell carcinoma

aPKC 在 Hedgehog 信号传导和基底细胞癌中的功能

• 批准号: 8633279
• 负责人: Scott Atwood
• 金额: $ 11.81万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-11 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633279
• 关键词: Allografting; Basal cell carcinoma; Binding Sites; Biochemistry; Biological Models; Cell Line; Cell Polarity; Cessation of life; Critiques; DNA Binding; Data; Defect; Development; Drug resistance; Environment; Epithelial; Erinaceidae; Exhibits; Gene Targeting; Genes; Genetic; Goals; Growth; Hair follicle structure; Human; Individual; Laboratories; Length; Ligand Binding; Link; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Molecular Biology; Mus; Mutation; Nature; Neoplasm Metastasis; Nuclear; Oncogenes; Organ; Organism; Pathway interactions; Pattern; Peptides; Phase; Phosphorylation; Post-Translational Protein Processing; Process; Proteins; Proteomics; Reagent; Research; Resistance; Retirement; Scaffolding Protein; Signal Pathway; Signal Transduction; Skin Cancer; Specificity; Stem cells; Testing; Therapeutic; Transcription Coactivator; Transducers; Tumor Cell Invasion; Vertebrates; Work; Writing; Zinc Fingers; atypical protein kinase C; drug discovery; human SMO protein; inhibitor/antagonist; meetings; migration; new therapeutic target; next generation sequencing; novel; novel therapeutics; overexpression; protein kinase C iota; public health relevance; receptor; smoothened signaling pathway; stem cell fate; therapeutic target; transcription factor; tumor; tumor growth

Project Summary/Abstract: Basal cell carcinoma (BCC) is the most prevalent cancer in the world and nearly half of US citizens are likely to develop this cancer before retirement. BCCs are invasive epithelial tumors that originate from activating mutations in the Hedgehog (Hh) pathway, an essential developmental pathway that has been implicated in approximately 25% of all human cancer deaths. Despite the critical nature of Hh signaling, how Hh mediates the impressive proliferative defects in cancers remain poorly understood. Hh pathway activation begins when Hh ligand binds and inhibits transmembrane receptor Patched1, allowing signal transducer Smoothened (Smo) to activate Gli transcription factors and amplify expression of Hh target genes. Smo inhibitors have recently gained approval for treatment of late advanced or metastatic BCC and exhibit potent tumor regression. While these inhibitors are effective in na¿ve tumors, aggressive tumors tend to develop early resistance to the drug, illustrating the need for new therapeutic targets. I have recently discovered that a critically important oncogene, atypical Protein Kinase C iota/lambda (aPKC-¿/¿), involved in stem cell fate choice during development of nearly all multicellular organisms is essential for high, sustained Hh pathway activation in BCCs. I have also shown pharmacological inhibition of aPKC suppresses murine BCC tumor growth and the growth of na¿ve and Smo-resistant BCC cells. The goal of my research is to determine the mechanisms that allow the polarity protein aPKC-¿/¿ to promote Hh pathway activation and na¿ve and Smo-resistant BCC growth. During the K99 phase, I will determine how phosphorylation of Gli by aPKC-¿/¿ alters target gene specificity to promote tumor growth, how BCC's regulate aPKC-¿/¿ activity, and test the therapeutic potential of additional novel aPKC-¿/¿ inhibitors for the treatment of na¿ve and resistant BCC. During the R00 phase, I will determine how aPKC-¿/¿ -dependent Gli1 responsive genes regulate tumor invasion and analyze aPKC-¿/¿ function in Smo-resistant BCCs. The results of this study will reveal conserved mechanisms that govern cell polarity and Hh signaling during BCC that will prove invaluable in generating novel therapeutics for the treatment of Hh-dependent cancers.

项目摘要/摘要：基底细胞癌 (BCC) 是世界上最常见的癌症，几乎 一半的美国公民可能在退休前患上这种癌症，这是一种侵袭性上皮肿瘤。 源自刺猬 (Hh) 途径的激活突变，这是一种重要的发育途径， 尽管 Hh 具有严重性，但约 25% 的人类癌症死亡与 Hh 相关。 信号传导，Hh 如何介导癌症中令人印象深刻的增殖缺陷仍然知之甚少。 当 Hh 配体结合并抑制跨膜受体 Patched1 时，通路激活开始，从而允许 信号转导器 Smoothened (Smo) 可激活 Gli 转录因子并放大 Hh 靶标的表达 Smo 基因抑制剂最近已获得批准用于治疗晚期或转移性 BCC 和 表现出有效的肿瘤消退作用。 ve 肿瘤，侵袭性肿瘤往往 对药物产生早期耐药性，这说明我最近需要新的治疗靶点。 发现一个极其重要的癌基因，非典型蛋白激酶 C iota/lambda (aPKC-¿/¿)，参与 几乎所有多细胞生物体发育过程中干细胞命运的选择对于高、持续的发育至关重要。 BCC 中的 Hh 通路激活也显示出 aPKC 的药理抑制作用可抑制小鼠。 BCC 肿瘤的生长和 na¿ ve 和 Smo 耐药的 BCC 细胞。 确定极性蛋白 aPKC-¿ 的机制/¿促进 Hh 通路激活和 呐ve 和 Smo 抗性 BCC 生长 在 K99 阶段，我将确定 Gli 如何磷酸化。 aPKC-¿ /¿改变靶基因特异性以促进肿瘤生长，BCC 如何调节 aPKC-¿ /¿活动，以及 测试其他新型 aPKC-¿ 的治疗潜力/¿用于治疗 na¿ 的抑制剂ve 和电阻 BCC。在R00阶段，我将确定如何aPKC-¿ /¿依赖Gli1反应基因调节肿瘤 入侵并分析aPKC-¿ /¿本研究的结果将揭示 Smo 抗性 BCC 中的保守功能。 BCC 期间控制细胞极性和 Hh 信号传导的机制将被证明在产生 治疗 Hh 依赖性癌症的新疗法。