MOLECULAR MECHANISMS OF HEDGEHOG SIGNALING

Hedgehog信号传导的分子机制

• 批准号: 6521170
• 负责人: ELIZABETH S SZTUL
• 金额: $ 20.39万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6521170
• 关键词: Drosophilidae; biological signal transduction; cell cell interaction; cell proliferation; confocal scanning microscopy; developmental genetics; endocytosis; epitope mapping; gene expression; gene interaction; genetic screening; homeobox genes; immunofluorescence technique; membrane proteins; molecular genetics; phenotype; protein binding; protein signal sequence; protein structure function; site directed mutagenesis; transcription factor

The long term objective of this research is to understand the molecular mechanisms that control cell-cell signaling in developing and adult tissues. Hedgehog (Hh) signaling proteins control cell fates and proliferation during animal development by regulating the specific gene expression. In vertebrates, Hh proteins pattern diverse tissues such as the developing limb, spinal column, and brain. The membrane protein Patched (Ptc) opposes Hh to inactivate specific gene expression. In Drosophila, ptc mutations cause misexpression of Hh target genes and result in abnormal development and cell proliferation. Mutations in a human homolog of ptc, PTCH1 lead to the very common skin tumor, basal cell carcinoma, and to the brain tumor, medulloblastoma. PTCH1 is also mutated in the basal cell nevus syndrome, an inherited disorder characterized by many developmental defects and tumors. The molecular mechanisms of Hh signal reception and transduction are largely unknown. Central to understanding the role of Hh signaling in development and disease is learning how Ptc functions and identifying proteins with which it interacts. Ptc is proposed to bind Hh proteins and to associate with and regulate, Smoothened, (Smo), a membrane protein required for Hh signaling. Ptc also sequesters Hh to limit its range of action. How and where Ptc mediates these important regulatory processes is not known. Ptc may function in vesicle movement as suggested by its sequence similarity to NPC1, a membrane protein implicated in the intracellular trafficking of cholesterol. The proposed studies will identify the critical functional domains of Ptc and characterize the cellular localization of Ptc and its interacting proteins following ligand binding. Using Drosophila, new components of Hh signaling will be identified by a genetic screen involving a specific ptc phenotype.

这项研究的长期目标是了解分子 在发育和成体中控制细胞-细胞信号的机制 纸巾。Hedgehog(HH)信号蛋白控制细胞命运和 通过调节特定基因在动物发育过程中的增殖 表情。在脊椎动物中，HH蛋白在不同的组织中形成图案 作为发育中的肢体、脊柱和大脑。膜蛋白 补丁(PTC)反对HH失活特定基因的表达。在……里面 果蝇，PTC突变导致HH靶基因错误表达和 导致异常发育和细胞增殖。A基因的突变 人类PTC、PTCH1的同源物导致非常常见的皮肤肿瘤，基底 细胞癌，以及脑肿瘤，髓母细胞瘤。Ptch1也是 一种遗传性疾病--基底细胞痣综合征发生突变 以许多发育缺陷和肿瘤为特征的。分子 HH信号的接收和转导机制在很大程度上还不清楚。 了解HH信号在发育和发育中的作用 疾病是学习PTC是如何工作的，并通过 它会相互作用。PTC被认为可以结合HH蛋白，并 结合并调节一种膜蛋白(Smo) HH信令所需的。PTC还隔离HH以限制其射程 行动的一部分。PTC如何以及在哪里调解这些重要的监管 进程尚不清楚。PTC可能在囊泡运动中起作用 与膜蛋白NPC1的序列相似性提示 与胆固醇在细胞内的运输有关。这个 拟议的研究将确定PTC的关键功能域 并研究了PTC的细胞定位及其相互作用 配基结合后的蛋白质。使用果蝇，新的成分 HH信号将通过涉及特定基因的遗传筛查来识别 PTC表型。