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: 8131855
• 负责人: TODD W RIDKY
• 金额: $ 11.95万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 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/8131855
• 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; JNK-activating protein kinase; 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/JNKK2/JNK MAP激酶cascade调节正常表皮稳态的生理信号传导，而这些途径的异常激活使这些途径驱动表皮肿瘤。 MEK和JNK在大多数自发的人表皮鳞状细胞癌中被激活，但是，在角质形成细胞中表达了每种蛋白质的两种同工型，并且尚未确定这些途径元素的明确功能作用。 MEK1无效小鼠是胚胎致死的，排除表皮表型的建立。但是，MEK2 NULL小鼠正常。这表明MEK1在功能上是占主导地位的，或者在功能上是MEK2的功能冗余。仅MEK1概括了增殖增加和分化减少的表皮RAS效应，这表明MEK1的主要作用。但是，MEK1/2具有高的同源性，而MEK2可以补偿MEK1损失的程度尚不清楚。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类表皮中的MEK1和MEK2。然后将定义MEK1/2支持RAS驱动的人表皮肿瘤发生的必要性和充分性。 JNK1和JNK2在表皮中似乎具有相反的作用。 JNK1的鼠表皮null是不塑性的，而JNK2无效的表皮具有高增殖性。然而，薄型JNK1无效组织比野生型皮肤更容易受到肿瘤的形成，而高增殖性JNK2无效组织对肿瘤发生抗性。 JNK1/2在正常人表皮中的作用将通过RNAi，主要阴性和药理抑制来定义。然后，将确定JNK1/2与RAS合作在驱动人表皮肿瘤形成方面的必要性和充分性。目标I和II是基于以下假设：MEK1/2和JNK1/2需要支持RAS驱动表皮肿瘤发生的关键组成部分。在拟议的融资期结束时，我们希望将MEK1/2和JNK1/2信号的重要性定义在正常的人表皮表皮稳态中，以及在RAS驱动的肿瘤中，作为对表皮生长和分化（包括癌症）人类疾病的未来治疗努力的基础。