Maf Molecular Interactions in Hematopoiesis

描述：(调查人员摘要)众所周知，具体的 转录因子驱动多能髓系祖细胞的承诺， 但大多数控制这些通路的调节电路仍然存在 未被开发的。了解转录因子在骨髓生成中的作用是 对于破译髓系细胞分化的调节至关重要。这个 拟议研究项目的长期目标是提供新的 关于控制血统选择和转录机制的信息 关于骨髓生成的规范，以及最终，这些如何被颠覆 产生单核/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Myb驱动的增殖物 程序。同时，c-maf介导单核细胞活化。 差异化信号，以及这些双重计划共同推动承诺 前体细胞分化为粒单核细胞系。因此，Maf 髓系细胞的功能可以被认为是Myb依赖的和 MYB非依赖性，单核细胞分化取决于由 这些相互依赖的项目中的每一个，都是由严重的 在缺乏c-Maf的动物中发现多系造血缺陷 蛋白。我们建议剖析分子机制并描绘出规则。 控制MAF抑制和转录因子相互作用的基因。的目标 我们的研究首先阐明了Myb和Myb之间的合作机制 MAF有助于单核细胞生成，可能还有助于其他 造血系(目标1)。对这些机制的理解将是 对定义下游基因的更广泛的造血学后果至关重要 受MAF和Myb的影响：MAF相互作用(目标2)。最后，因为Maf是一个 一个密切相关的多基因家族的成员，具有不同的表达模式， 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转录的一般手段 在表达Maf蛋白的不同组织中进行控制，因此可能是 在更广泛的发展背景下具有相关性。

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.