MYELOID REGULATION OF CD18 TRANSCRIPTION

分化与严格调控的时间， 定量和组织特异性基因表达。 知识 在骨髓分化过程中基因表达的分子控制是 由于缺乏用于该过程的明确定义的模型而受到限制。 CD 18是 白细胞整联蛋白的β链，一个抗原家族， 介导对免疫至关重要的细胞粘附功能， 炎症反应。 CD 18表达不足导致严重的 白细胞粘附缺陷症（Leukocyte Adhesion Deficiency，LAD） 因为 CD 18转录在髓样分化期间显著增加， 该基因为谱系特异性基因提供了相关模型 在骨髓分化过程中的转录。 CD 18基因已经被 克隆，并分离启动子和侧翼区。 CD18 启动子含有潜在的AP-1、CREB和Oct位点; 白细胞特异性转录因子PU.1;一种假定的髓样 特异性元件和潜在视黄酸响应元件。 的 CD 18启动子以白细胞特异性的方式指导表达， 对佛波酯和维甲酸诱导的髓样 分化 通过顺序缺失，编码高水平的区域 骨髓活性是局部的。 与该区域的两个位点结合， PU.1是CD 18启动子的高水平髓样活性所必需的。 启动子的扫描突变定位了其他阳性和 负调控因素。 许多核蛋白与CD 18结合 电泳迁移率变动分析（EMSA）和DNA酶I中的启动子 脚印 其中一些因素，包括其他ets家族成员 和Sp1转录因子，现已被鉴定。 这 一项提案旨在确定顺式DNA元件和反式作用元件， 调节CD 18表达的因子。 瞬时和稳定横断 将用于定义控制谱系的功能性DNA元件- 特异性和诱导性CD 18表达EMSA和DNA酶I足迹法将 用于进一步表征与CD 18结合的核因子 调控DNA元件。 更好地了解分子控制 CD 18表达水平的变化可能对肿瘤的发病机制和治疗产生影响。 小伙子 因为某些急性白血病的染色体重排 产生类似转录因子的新蛋白质， 反式作用因子可能在白血病的发病中起重要作用。

Differentiation is intimately linked to tightly regulated temporal, quantitative,and tissue-specific gene expression. Knowledge of the molecular control of gene expression during myeloid differentiation is limited by a paucity of well defined models for this process. CD18 is the Beta chain of the leukocyte integrins, a family of antigens which mediate cell adhesive functions that are critical to the immune and inflammatory responses. In adequate expression of CD18 causes the severe immunodeficiency known as Leukocyte Adhesion Deficiency (LAD). Because CD18 transcription increases markedly during myeloid differentiation, this gene provides a relevant model for lineage-specific gene transcription during myeloid differentiation. The CD18 gene has been cloned, and the promoter and flanking regions isolated. The CD18 promoter contains potential AP-1, CREB, and Oct sites; a binding site for the leukocyte specific transcription factor PU.1; a putative myeloid specific element; and a potential retinoic acid response element. The CD18 promoter directs expression in a leukocyte-specific manner, and is responsive to phorbol ester and retinoic acid induced myeloid differentiation. By sequential deletion, a region encoding high level myeloid activity was localized. Binding to two sites in this region by PU.1 is required for high level myeloid activity of the CD18 promoter. Scanning mutagenesis of the promoter localized other positive and negative regulatory elements. Numerous nuclear proteins bind to the CD18 promoter in electrophoretic mobility shift assay (EMSA) and DNAse I footprinting. Some of these factors, including other ets family members and the Sp1 transcription factor, have now been identified. This proposal seeks to identify the cis DNA elements and the trans acting factors which regulate CD18 expression. Transient and stable transection will be used to define the functional DNA elements which control lineage- specific and inducible CD18 expression EMSA and DNAse I footprinting will be used to further characterize nuclear factors which bind to CD18 regulatory DNA elements. Greater understanding of the molecular control of CD18 expression may have an impact on the pathogenesis and therapy of LAD. Because chromosomal rearrangements in some forms of acute leukemia generate novel proteins which resemble transcription factors, myeloid trans acting factors may play an important etiologic role in leukemia.