MAPK PATHWAY REGULATION OF MYELOID CELL DIFFERENTIATION

骨髓细胞分化的 MAPK 通路调控

• 批准号: 2684637
• 负责人: PAUL S SHAPIRO
• 金额: $ 1.52万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2684637
• 关键词: autocrine; cell differentiation; developmental genetics; hematopoiesis; mitogen activated protein kinase; myeloid stem cell; tissue /cell culture; transcription factor

The goal of this proposal is to explore the importance of the MAPK pathway in regulating myeloid cell differentiation. The MAPK pathway is a signal transduction module downstream of p21 ras, which involves raf kinase activation of MAP kinase kinase (MAPKK) and MAPKK activation of MAPK. MAPK targets many signalling molecules including protein kinases, receptors, phospholipases, and transcription factors. Preliminary results obtained in this lab demonstrate that overexpression of constitutively active MAPKK mutants causes K562 cell differentiation. K562 cells are a useful tool to study cell differentiation because they are multipotent. For example, treatment with phorbol esters causes K562 cells differentiation into platelet precursor megakaryocytes. In contrast, upon treatment with erythropoietin, k562 cells become erythroid. Thus, the hypothesis that this proposal will address is that the MAPK pathway is necessary and sufficient for determining K562 cell differentiation towards a megakaryocyte or erythroid lineage. Studies will be carried out to identify the cell lineages induced by overexpression of active MAPKK and to determine whether MAPK activation is required for these events. The hypothesis that the kinetics or magnitude of MAPKK activation influences cell differentiation will be tested. And finally, mechanisms of MAPKK-induced differentiation will be explored by testing whether differentiation requires the production of an autocrine factor or occurs directly through the activation of lineage-specific transcription factors. Completion of these studies will provide important information about the mechanisms that govern cell differentiation.

该提案的目标是探讨 MAPK 的重要性 调节骨髓细胞分化的途径。 MAPK途径是 p21 ras下游的信号转导模块，涉及raf MAP 激酶激酶 (MAPKK) 的激酶激活和 MAPKK 激活 映射。 MAPK 靶向许多信号分子，包括蛋白激酶、 受体、磷脂酶和转录因子。初步结果 本实验室获得的结果表明，组成型的过度表达 活性 MAPKK 突变体导致 K562 细胞分化。 K562 细胞是 研究细胞分化的有用工具，因为它们是多能的。 例如，用佛波酯治疗会导致 K562 细胞 分化为血小板前体巨核细胞。相比之下，根据 用促红细胞生成素治疗，k562细胞变成红细胞。因此， 该提案将解决的假设是 MAPK 途径是 确定 K562 细胞分化的必要和充分条件 朝向巨核细胞或红细胞谱系。 将进行研究 鉴定由活性物质过度表达诱导的细胞谱系 MAPKK 并确定这些是否需要 MAPK 激活 事件。 MAPKK 激活的动力学或幅度的假设 将测试对细胞分化的影响。最后，机制 将通过测试是否可以探索 MAPKK 诱导的分化的作用 分化需要产生自分泌因子或发生 直接通过谱系特异性转录的激活 因素。完成这些研究将提供重要信息 关于控制细胞分化的机制。

项目成果

Activation of ERK and JNK1 MAP kinases in cultured lung tissue.

培养肺组织中 ERK 和 JNK1 MAP 激酶的激活。

• DOI: 10.1152/ajplung.1997.273.2.l459
• 发表时间: 1997
• 期刊: The American journal of physiology
• 作者: Shapiro,P;Absher,PM;Posada,JP;Evans,JN
• 通讯作者: Evans,JN

Activation of the MKK/ERK pathway during somatic cell mitosis: direct interactions of active ERK with kinetochores and regulation of the mitotic 3F3/2 phosphoantigen.

• DOI: 10.1083/jcb.142.6.1533
• 发表时间: 1998-09-21
• 期刊: JOURNAL OF CELL BIOLOGY
• 影响因子: 7.8
• 作者: Shapiro, P S;Vaisberg, E;Hunt, A J;Tolwinski, N S;Whalen, A M;McIntosh, J R;Ahn, N G
• 通讯作者: Ahn, N G