Characterization of Ras-Driven Human Epidermal Neoplasia

Ras 驱动的人类表皮肿瘤的特征

• 批准号: 8236968
• 负责人: PAUL KHAVARI
• 金额: $ 33.32万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-05 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8236968
• 关键词: Actinic keratosis; Address; Adhesions; Basement membrane; Binding; Breast; Carcinoma; Cdc25C protein; Cell Cycle; Cell Cycle Progression; Cell Proliferation; Cell division; Cell surface; Collagen; Collagen Type VII; Colon; Cutaneous; Cyclin D1; Disease; Epidermis; Epithelial; Evolution; Extracellular Space; Funding; G2/M Arrest; Gap Junctions; Genes; Genetic; Homeostasis; Human; Hyperplasia; Informatics; Integrins; Laminin; Ligands; Light; M cell; MAP Kinase Kinase Kinase; Maintenance; Malignant Neoplasms; Mediating; Mediator of activation protein; Membrane Proteins; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Mitosis; Modeling; Mutation; Neoplasms; Oncogenes; Pathologic; Pathway Analysis; Pathway interactions; Process; Proteins; Regulation; Regulatory Pathway; Research Design; Role; Signal Pathway; Signal Transduction; Skin; Skin Tissue; Squamous cell carcinoma; Therapeutic; Tissues; base; cyclin G1; design; in vivo; insight; laminin-5; neoplastic; novel strategies; protein function; public health relevance; receptor; research study; skin squamous cell carcinoma; tumor; tumor progression

DESCRIPTION (provided by applicant): Insight into control of epidermal proliferation is important for understanding both skin homeostasis and disease. Uncontrolled epidermal proliferation characterizes the 2 most common cancers in the U.S., including epidermal squamous cell carcinoma (SCC). Functionally characterizing the role of identified signaling pathways and basement membrane proteins in normal human skin tissue and in epidermis undergoing progression from pre-neoplasia towards cancer using new skin models is a focus of this AR43799 competing renewal. First, we plan to characterize the function of downstream components of the Ras/MAPK cascade in human skin tissue. We will first determine if Ras-mediated control of proliferation and progression from pre-neoplasia proceeds down the classical Ras/Erk MAPK cascade by studying the necessity and sufficiency of Erk1 (p44ERK1) and Erk2 (p42ERK2) in this process. To characterize how the Ras/MAPK pathway controls cell cycle progression in human epidermis, we will define the role of Ras/MAPK-targeted cell cycle regulators that act in both G1/S and G2/M phases of the cell cycle, with a special focus on the newly identified role of Erk-induced CDC25C activation in G2/M cell cycle progression. These studies are designed to extend characterization of Ras/MAPK cascade regulation of human epidermal proliferation to downstream levels that include Erk MAPKs and their cell cycle targets. Second, we plan to define the role of specific epidermal basement membrane proteins in homeostasis and in Ras-driven progression from pre-neoplasia. We will determine if recently identified invasion-promoting sequences of collagen VII mediate binding to laminin 332 (laminin-5) and normal epidermal adhesion. We will also characterize the role of the 21 integrin subunit in proliferation and in epidermal tumor progression. To do this, we will begin by characterizing the 1 integrin subunits and stromal ligands involved in this process. These studies are designed to elucidate mechanisms of basement membrane protein function in epidermal homeostasis and in progression towards neoplasia. At the end of the proposed funding period, we hope to have characterized Ras-driven mechanisms regulating epidermal homeostasis, proliferation and the progression of human epidermis towards neoplasia. PUBLIC HEALTH RELEVANCE: Control of cell proliferation in the skin and other tissues is critical for normal body maintenance and avoidance of disease, including cancer. New approaches to study the regulatory pathways controlling proliferation in human skin tissue have identified a dominant role for the Ras/MAPK signaling pathway in normal and pathological epidermal proliferation. A deeper analysis of how this pathway regulates the cell division cycle and how it interacts with signals coming from the cell surface and extracellular space is designed to shed light on normal and pathologic control of proliferation in skin.

描述（由申请人提供）：深入了解表皮增殖的控制对于理解皮肤稳态和疾病很重要。不受控制的表皮增殖是美国最常见的两种癌症的特征，其中包括表皮鳞状细胞癌 (SCC)。使用新的皮肤模型对已识别的信号通路和基底膜蛋白在正常人类皮肤组织和从肿瘤前期向癌症进展的表皮中的作用进行功能表征是 AR43799 竞争更新的重点。首先，我们计划表征 Ras/MAPK 级联下游成分在人类皮肤组织中的功能。我们将首先通过研究 Erk1 (p44ERK1) 和 Erk2 (p42ERK2) 在此过程中的必要性和充分性，确定 Ras 介导的对肿瘤前期增殖和进展的控制是否沿着经典 Ras/Erk MAPK 级联进行。为了表征 Ras/MAPK 通路如何控制人表皮细胞周期进程，我们将定义在细胞周期的 G1/S 和 G2/M 阶段发挥作用的 Ras/MAPK 靶向细胞周期调节剂的作用，特别关注新发现的 Erk 诱导的 CDC25C 激活在 G2/M 细胞周期进程中的作用。这些研究旨在将人类表皮增殖的 Ras/MAPK 级联调节的表征扩展到下游水平，包括 Erk MAPK 及其细胞周期靶标。其次，我们计划确定特定表皮基底膜蛋白在稳态和 Ras 驱动的肿瘤前期进展中的作用。我们将确定最近发现的 VII 型胶原蛋白的侵袭促进序列是否介导与层粘连蛋白 332（层粘连蛋白-5）的结合和正常表皮粘附。我们还将描述 21 整合素亚基在增殖和表皮肿瘤进展中的作用。为此，我们将首先表征此过程中涉及的 1 整合素亚基和基质配体。这些研究旨在阐明基底膜蛋白在表皮稳态和肿瘤进展中的功能机制。在拟议的资助期结束时，我们希望能够表征 Ras 驱动的调节表皮稳态、增殖和人类表皮向肿瘤进展的机制。 公共卫生相关性：控制皮肤和其他组织中的细胞增殖对于正常的身体维护和避免疾病（包括癌症）至关重要。研究控制人类皮肤组织增殖的调控途径的新方法已经确定了 Ras/MAPK 信号传导途径在正常和病理性表皮增殖中的主导作用。对该途径如何调节细胞分裂周期以及它如何与来自细胞表面和细胞外空间的信号相互作用进行更深入的分析，旨在揭示皮肤增殖的正常和病理控制。