Opposing Roles for MEK/ERK in Differentiation & Leukemia

MEK/ERK 在分化中的相反作用

• 批准号: 7496745
• 负责人: Daniel E Johnson
• 金额: $ 3.87万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7496745
• 关键词: Acute Promyelocytic Leukemia; Adoptive Transfer; Bone Marrow; Bone Marrow Cells; CD34 gene; Cell Line; Cell Lineage; Cell Survival; Chemicals; Condition; Defect; Development; Differentiation Therapy; Enzymes; Exhibits; Fostering; Generations; Growth; Hematopoietic; Human; In Vitro; Lead; MEK inhibition; MEKs; Mediating; Modeling; Mus; Myelogenous; Myeloid Cells; Myeloid Leukemia; Myelopoiesis; Oncogene Proteins; Pathway interactions; Play; Research Personnel; Role; Signal Pathway; Signal Transduction Pathway; Small Interfering RNA; Stem cells; System; Testing; Tetracycline; Tetracyclines; Transgenic Mice; Transgenic Model; cell growth; cytokine; human MAP2K1 protein; in vivo; leukemia; leukemogenesis; mouse model; novel; progenitor; programs; retinoic acid receptor alpha

Myeloid leukemias are characterized by aberrant blockade of differentiation due to expression of leukemic oncoproteins such as PML/RAR-alpha. Elucidation of the mechanisms responsible for normal myeloid differentiation will further our understanding of differentiation blockades in leukemias, and foster the development of novel differentiation therapies. Thus, our long-term objective is to define the intracellular signaling pathways that lead to myeloid differentiation, and the role these pathways play in leukemogenesis. In preliminary studies we have observed rapid and prolonged activation of the MEK/ERK signal transduction pathway during myeloid differentiation. Furthermore, MEK/ERK activation was required for differentiation in myeloid cell lines. This contrasts with known roles for MEK/ERK activation in proliferation and survival, and constitutive MEK/ERK hyperactivation in myeloid leukemias. Together, these studies suggest a dichotomy of roles for MEK/ERK activation: promoting differentiation under normal conditions, and transformation under conditions where differentiation is blocked. Therefore, we hypothesize that prolonged activation of the MEK/ERK pathway is critically important for cytokine-induced myeloid differentiation. We further hypothesize that activation of the MEK/ERK pathway cooperates with differentiation-inhibiting leukemic oncoproteins to promote leukemogenesis. To test this hypothesis, we will: 1) elucidate the importance of MEK/ERK activation during cytokine-induced myeloid differentiation of myeloid cell lines and primary cultures of normal murine myeloid progenitors; 2) determine the functional consequences of MEK/ERK activation during cytokine-induced myeloid differentiation; 3) examine whether MEK/ERK activation promotes myeloid differentiation in vivo through the generation of transgenic mice that inducibly express constitutively active MEK enzyme in myeloid lineage cells; and 4) determine whether MEK/ERK activation cooperates with expression of PML/RAR-alpha to promote myeloid leukemogenesis.

髓性白血病的特征在于由于白血病细胞的表达而导致的分化的异常阻断。 癌蛋白如PML/RAR-α。阐明正常髓系细胞的机制 分化将进一步加深我们对白血病分化阻滞的理解， 开发新的分化疗法。因此，我们的长期目标是确定细胞内 导致骨髓分化的信号通路，以及这些通路在白血病发生中的作用。 在初步研究中，我们观察到MEK/ERK信号的快速和长期激活， 在骨髓分化过程中的转导途径。此外，MEK/ERK激活是必需的， 骨髓细胞系的分化。这与MEK/ERK活化在增殖中的已知作用形成对比 和生存，以及髓系白血病中的组成性MEK/ERK过度活化。这些研究一起 提示MEK/ERK活化作用的二分法：在正常条件下促进分化， 以及在分化被阻断的条件下转化。因此，我们假设 MEK/ERK通路的延长激活对于精氨酸诱导的髓样白血病至关重要。 分化我们进一步假设MEK/ERK通路的激活与 分化抑制白血病癌蛋白促进白血病发生。为了验证这个假设，我们将： 1)阐明MEK/ERK活化在苦参碱诱导的骨髓分化过程中的重要性。 正常鼠骨髓祖细胞的骨髓细胞系和原代培养物; 2）确定功能性骨髓祖细胞的功能， 3）检测在丝氨酸诱导的髓样分化过程中MEK/ERK活化的结果; MEK/ERK激活通过产生转基因小鼠促进体内髓样分化， 在髓系细胞中诱导表达组成型活性MEK酶;和4）确定是否 MEK/ERK活化与PML/RAR-α表达协同促进髓系白血病发生。