Characterization of Ras-Driven Human Epidermal Neoplasia

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都很重要。不受控制的表皮增生是美国两种最常见的癌症的特征，包括表皮鳞状细胞癌（SCC）。使用新的皮肤模型功能性表征正常人皮肤组织和表皮中鉴定的信号通路和基底膜蛋白的作用，这些表皮经历从肿瘤前向癌症的进展，这是AR 43799竞争性更新的焦点。首先，我们计划在人体皮肤组织中的Ras/MAPK级联下游组件的功能的特点。我们将首先通过研究Erk 1（p44 ERK 1）和Erk 2（p42 ERK 2）在这一过程中的必要性和充分性来确定Ras介导的增殖控制和肿瘤前病变的进展是否沿着经典的Ras/Erk MAPK级联反应进行。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Ras/MAPK靶向的细胞周期调节剂在细胞周期G1/S和G2/M期的作用，特别关注新发现的ERK诱导的CDC 25 C激活在G2/M细胞周期进程中的作用。这些研究旨在将Ras/MAPK级联调节人表皮增殖的表征扩展到下游水平，包括Erk MAPK及其细胞周期靶点。其次，我们计划确定特定的表皮基底膜蛋白在体内平衡和Ras驱动的肿瘤前进展中的作用。我们将确定是否最近确定的入侵促进序列的VII型胶原介导层粘连蛋白332（层粘连蛋白-5）和正常的表皮粘附结合。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，我们将开始通过表征1整合素亚基和基质配体参与这一过程。这些研究旨在阐明基底膜蛋白在表皮稳态和肿瘤形成过程中的作用机制。在拟议的资助期结束时，我们希望能够表征Ras驱动的机制，调节表皮稳态，增殖和人类表皮向肿瘤的进展。 公共卫生相关性：控制皮肤和其他组织中的细胞增殖对于维持正常身体和避免疾病（包括癌症）至关重要。研究控制人类皮肤组织增殖的调节途径的新方法已经确定了Ras/MAPK信号通路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，旨在阐明皮肤增殖的正常和病理控制。

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.