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动态平衡和疾病都很重要。美国最常见的两种癌症是不受控制的表皮增殖，包括表皮鳞状细胞癌(SCC)。使用新的皮肤模型从功能上表征已识别的信号通路和基底膜蛋白在正常皮肤组织和经历从肿瘤前病变向癌症进展的表皮中的作用是此次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)在这一过程中的必要性和充分性来确定RAS介导的对肿瘤前病变的增殖和进展的控制是否沿着经典的RAS/ERK MAPK级联反应进行。为了研究RAS/MAPK通路如何控制人表皮细胞周期进程，我们将确定RAS/MAPK靶向细胞周期调节因子在细胞周期的G1/S和G2/M期的作用，特别关注最近发现的ERK诱导的CDC25C激活在G2/M细胞周期进展中的作用。这些研究旨在将RAS/MAPK对人表皮增殖的级联调控扩展到下游水平，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动态平衡和RAS驱动的肿瘤前病变进展中的作用。我们将确定最近发现的VII型胶原的侵袭促进序列是否介导了与层粘连蛋白332(LN-5)的结合和正常的表皮黏附。我们还将描述21整合素亚单位在增殖和表皮肿瘤进展中的作用。为了做到这一点，我们将从鉴定参与这一过程的1整合素亚基和基质配体开始。这些研究旨在阐明基底膜蛋白在表皮动态平衡和肿瘤进展中的作用机制。在拟议的资助期结束时，我们希望能够表征RAS驱动的调节表皮动态平衡、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包括癌症在内的疾病至关重要。研究控制人类皮肤组织增殖的调控通路的新方法已经证实，Ras/MAPK信号通路在正常和病理性表皮增殖中起主导作用。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。

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.