Maf Molecular Interactions in Hematopoiesis

描述：（研究者摘要）已经明确， 转录因子驱动多能骨髓祖细胞的定型， 但大多数控制这些通路的调节回路 未开发的了解转录因子在骨髓细胞生成中的作用是 这对于解释髓样细胞分化的调节至关重要。的 该研究项目的长期目标是提供新的 关于控制谱系选择的转录机制的信息， 骨髓生成的规范，并最终，如何这些可以被颠覆， 产生单核细胞/巨噬细胞系统的疾病。在骨髓生成过程中， c-Myb的特异性靶点被c-Maf转录选择性抑制 因子，从而脱离前体细胞的Myb驱动的增殖 程序.同时，c-Maf介导单核细胞活化， 差异化信号，这些双重计划共同推动了承诺 以及前体细胞向骨髓单核细胞谱系的分化。因此，Maf 在骨髓细胞中的功能可以被视为Myb依赖性和 而单核细胞的分化依赖于 这些相互依赖的程序中的每一个，一个假设支持的严重 在缺乏c-Maf的动物中发现的多系造血缺陷 蛋白我们建议剖析分子机制， 控制Maf抑制和转录因子相互作用。的目标 我们的研究首先要阐明Myb和 Maf有助于单核细胞生成，也许还有助于其他 造血谱系（Aim 1）。对这些机制的理解将是 对于定义下游基因的更广泛的造血后果至关重要， 受Maf和Myb：Maf相互作用的影响（目的2）。最后，因为Maf是一个 具有不同表达模式的密切相关的多基因家族的成员， Maf可能与其他序列特异性转录相互作用， 因子和辅助分子构成了转录的一般手段， 在Maf蛋白表达的不同组织中控制，因此可能是 在更广泛的发展背景下。

DESCRIPTION: (Investigator's abstract) It is well established that specific transcription factors drive the commitment of multipotent myeloid progenitors, but most of the regulatory circuits controlling these pathways remain unexplored. Understanding transcription factor function in myelopoiesis is essential for deciphering the regulation of myeloid cell differentiation. The long-term objectives of the proposed research project are to provide new information on the transcriptional mechanisms governing lineage choice and specification in myelopoiesis and ultimately, how these can be subverted to produce diseases of the monocyte/macrophage system. During myelopoiesis, specific targets of c-Myb are selectively repressed by the c-Maf transcription factor, thereby disengaging the precursor cell's Myb-driven proliferative program. Simultaneously, c-Maf mediates the activation of monocytic differentiation signals, and together these dual programs propel the commitment and differentiation of precursor cells to the myelomonocytic lineage. Thus, Maf function in myeloid cells can be viewed as both Myb-dependent and Myb-independent, and monocytic differentiation depends upon events triggered by each of these interdependent programs, a hypothesis supported by the severe multilineage hematopoietic defects found in animals that lack the c-Maf protein. We propose to dissect the molecular machinery and delineate the rules that govern Maf repression and transcription factor interaction. The goals of our research are to first clarify the cooperative mechanisms by which Myb and Maf contribute to monocytopoiesis and perhaps to the development of other hematopoietic lineages (Aim 1). An understanding of these mechanisms will be critical to defining the broader hematopoietic consequences of downstream genes affected by Maf and Myb:Maf interactions (Aim 2). Finally, because Maf is a member of a closely related multigene family with distinct expression patterns, it is possible that Maf interactions with other sequence-specific transcription factors and accessory molecules constitute a general means of transcriptional control in diverse tissues where Maf proteins are expressed, and thus may be relevant in a broader developmental context.