Characterization of Ras-Driven Human Epidermal Neoplasia

描述（由申请人提供）：深入了解表皮增生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最常见的两种癌症的特征，包括表皮鳞状细胞癌（SCC）。利用新的皮肤模型，从功能上表征正常人类皮肤组织和表皮从肿瘤前期发展到癌症的过程中已识别的信号通路和基底膜蛋白的作用，是AR43799竞争更新的重点。首先，我们计划表征Ras/MAPK级联下游组分在人体皮肤组织中的功能。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要性来确定Ras介导的肿瘤前期增殖和进展的控制是否沿着经典的Ras/Erk MAPK级联进行。为了描述Ras/MAPK通路如何控制人类表皮细胞周期进程，我们将定义Ras/MAPK靶向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erk诱导的CDC25C激活在G2/M细胞周期进程中的新发现的作用。这些研究旨在将Ras/MAPK级联调节人类表皮增殖的特性扩展到下游水平，包括Erk MAPKs及其细胞周期靶点。其次，我们计划确定特定表皮基底膜蛋白在稳态和肿瘤前期ras驱动进展中的作用。我们将确定最近发现的促进侵袭的胶原蛋白VII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。要做到这一点，我们将开始表征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发展过程中的功能机制。在拟议的资助期结束时，我们希望能够描述ras驱动的调节表皮稳态、增殖和人类表皮向肿瘤发展的机制。

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.