Physiologic Function of RAS Effectors MEK 1/2 on Epidermal Differentiation

RAS效应器MEK 1/2对表皮分化的生理功能

基本信息

批准号：
7210929
负责人：
TODD W RIDKY
金额：
$ 11.95万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-10 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7210929
关键词：
Automobile Driving Complement Coupled Data Development Differentiation and Growth Disease Disruption Dominant-Negative Mutation Embryo Epidermis Epithelial Funding Future Genes Genetic Goals Guanosine Triphosphate Phosphohydrolases Homeostasis Human Indium Integrins Invasive Knockout Mice MAP Kinase Gene MAP Kinase Modules MAP2K1 gene MAPK8 gene MAPK9 gene MEK inhibition MEKKs MEKs Maintenance Malignant - descriptor Malignant Neoplasms Mediating Modeling Mus Neoplasms Oncogenic Pathway interactions Phenotype Physiological Play Protein Isoforms Proteins RNA Interference Ras/Raf Regulation Relative (related person)Research Personnel Resistance Role Signal Pathway Signal Transduction Signaling Protein Skin Squamous cell carcinoma Stimulus Therapeutic Therapeutic Intervention Tissues base human tissue inhibitor/antagonist keratinocyte programs response tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Physiologic signaling through the Ras/Raf/MEK/ERK and parallel MEKK/JNKK2/JNK MAP kinase cascades regulates normal epidermal homeostasis, while aberrant activation of these pathways drives epidermal neoplasia. MEK and JNK are activated in a majority of spontaneous human epidermal squamous cell carcinomas, however, two isoforms of each protein are expressed in keratinocytes, and clear functional roles for these pathway elements in human epidermis have not been established. MEK1 null mice are embryonic lethal, precluding establishment of epidermal phenotypes; however, MEK2 null mice are normal. This suggests that MEK1 is either functionally dominant, or functionally redundant with MEK2. The epidermal Ras effects of increased proliferation and decreased differentiation are recapitulated only by MEK1, suggesting a primary role for MEK1. However, MEK1/2 share high homology, and the extent to which MEK2 can compensate for MEK1 loss is unknown. To clarify the relative functional roles of MEK1/2 in human epidermal homeostasis, as well as in epidermal tumorigenesis, we will use complementary RNAi and pharmacologic approaches to inhibit MEK1 and MEK2 in human epidermis. The necessity and sufficiency of MEK1/2 to support Ras driven human epidermal tumorigenesis will then be defined. JNK1 and JNK2 appear to have opposing effects in epidermis. Murine epidermis null for JNK1 is hypoplastic, while JNK2 null epidermis is hyperproliferative. However, the thin hypoplastic JNK1 null tissue is more susceptible than wild type skin to tumor formation, while the hyperproliferative JNK2 null tissue is resistant to tumorigenesis. JNK1/2 roles in normal human epidermis will be defined through RNAi, dominant negative and pharmacologic inhibition. The necessity and sufficiency of JNK1/2 to cooperate with Ras in driving human epidermal tumor formation will then be determined. Aims I and II are based on the hypothesis that MEK1/2 and JNK1/2 are required to support key components of Ras driven epidermal tumorigenesis. At the completion on the proposed funding period, we hope to have defined the importance of MEK1/2 and JNK1/2 signaling in both normal human epidermal homeostasis, and in Ras-driven tumorigenesis as a basis for future therapeutic efforts for human disorders of epidermal growth and differentiation, including cancer.

描述（由申请人提供）：通过 Ras/Raf/MEK/ERK 和平行的 MEKK/JNKK2/JNK MAP 激酶级联的生理信号传导调节正常的表皮稳态，而这些途径的异常激活则驱动表皮瘤形成。 MEK 和 JNK 在大多数自发性人表皮鳞状细胞癌中被激活，然而，每种蛋白的两种亚型在角质形成细胞中表达，并且这些途径元件在人表皮中的明确功能作用尚未确定。 MEK1缺失小鼠胚胎是致命的，无法建立表皮表型；然而，MEK2 缺失小鼠却是正常的。这表明 MEK1 要么在功能上占主导地位，要么在功能上与 MEK2 冗余。增殖增加和分化减少的表皮 Ras 效应仅由 MEK1 重现，表明 MEK1 的主要作用。然而，MEK1/2具有高度同源性，MEK2能在多大程度上补偿MEK1的损失尚不清楚。为了阐明 MEK1/2 在人表皮稳态以及表皮肿瘤发生中的相对功能作用，我们将使用互补的 RNAi 和药理学方法来抑制人表皮中的 MEK1 和 MEK2。然后将定义 MEK1/2 支持 Ras 驱动的人类表皮肿瘤发生的必要性和充分性。 JNK1 和 JNK2 似乎在表皮中具有相反的作用。 JNK1 缺失的小鼠表皮发育不全，而 JNK2 缺失的表皮过度增殖。然而，薄的发育不全的JNK1缺失组织比野生型皮肤更容易形成肿瘤，而过度增殖的JNK2缺失组织对肿瘤发生有抵抗力。 JNK1/2 在正常人表皮中的作用将通过 RNAi、显性失活和药理学抑制来定义。随后将确定JNK1/2与Ras配合驱动人类表皮肿瘤形成的必要性和充分性。目标 I 和 II 基于这样的假设：MEK1/2 和 JNK1/2 是支持 Ras 驱动的表皮肿瘤发生的关键成分所必需的。在拟议的资助期结束时，我们希望确定 MEK1/2 和 JNK1/2 信号在正常人类表皮稳态和 Ras 驱动的肿瘤发生中的重要性，作为未来治疗人类表皮疾病的基础。生长和分化，包括癌症。