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

• 批准号: 7664424
• 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
• 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/7664424
• 关键词: Automobile Driving; Complement; Coupled; Data; Development; Differentiation and Growth; Disease; Dominant-Negative Mutation; Embryo; Epidermis; Epithelial; Funding; Future; Genes; Genetic; Goals; Guanosine Triphosphate Phosphohydrolases; Homeostasis; Human; Indium; Integrins; 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

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MEKK/JNKK 2/JNK MAP激酶级联的生理信号传导调节正常表皮稳态，而这些途径的异常激活驱动表皮瘤形成。MEK和JNK在大多数自发性人表皮鳞状细胞癌中被激活，然而，每种蛋白质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。MEK 1敲除小鼠是胚胎致死的，排除了表皮表型的建立;然而，MEK 2敲除小鼠是正常的。这表明MEK 1在功能上占主导地位，或者与MEK 2在功能上冗余。表皮Ras的增殖增加和分化降低的作用仅由MEK 1重演，表明MEK 1的主要作用。然而，MEK 1/2具有高度同源性，并且MEK 2可以在多大程度上补偿MEK 1的损失尚不清楚。为了阐明MEK 1/2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RNAi和药理学方法来抑制人表皮中的MEK 1和MEK 2。然后将定义MEK 1/2支持Ras驱动的人表皮肿瘤发生的必要性和充分性。JNK 1和JNK 2似乎在表皮中具有相反的作用。JNK 1缺失的小鼠表皮是发育不良的，而JNK 2缺失的表皮是过度增殖的。然而，薄的发育不良的JNK 1无效组织比野生型皮肤更易受肿瘤形成的影响，而过度增殖的JNK 2无效组织对肿瘤发生具有抗性。JNK 1/2在正常人表皮中的作用将通过RNAi、显性阴性和药理学抑制来定义。JNK 1/2与Ras合作驱动人表皮肿瘤形成的必要性和充分性将被确定。目的I和II是基于这样的假设，即需要MEK 1/2和JNK 1/2来支持Ras驱动的表皮肿瘤发生的关键组分。在拟议的资助期结束时，我们希望已经确定了MEK 1/2和JNK 1/2信号在正常人表皮稳态和Ras驱动的肿瘤发生中的重要性，作为未来治疗人类表皮生长和分化障碍（包括癌症）的基础。