ICSBP Function During Myeloid Differentiation

ICSBP 在骨髓分化过程中的功能

基本信息

批准号：
7113138
负责人：
Elizabeth Ann Eklund
金额：
$ 29.04万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-01 至 2008-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Two observations suggest that the Interferon Consensus Sequence Binding Protein (ICSBP) is necessary for normal myeloid differentiation. The first observation is that ICSBP -/- mice have myeloid expansion and impaired immune function. This suggests that ICSBP is necessary for progression of differentiation. The second observation is that ICSBP expression is decreased in human myeloid malignancy, and 1CSBP -/- mice develop myeloid leukemia. This suggests that ICSBP is a "leukemia suppressor", during myeloid differentiation. We found that tyrosine phosphorylated ICSBP interacts with PU.1, Interferon Regulatory Factor 1, and the CREB-binding protein, during late myeloid differentiation. This interaction activates genes encoding the respiratory burst oxidase proteins, gp91phox and p67phoX. These results suggest that ICSBP activates transcription of genes that confer the mature phagocyte phenotype. In contrast, non-tyrosine phosphorylated ICSBP represses Bcl-XL expression in undifferentiated myeloid cells. This suggests that ICSBP influences initiation of apoptosis during early differentiation. Therefore, ICSBP tyrosine phosphorylation, which occurs during myelopoiesis, alters protein-DNA and protein-protein interactions. Based on these observations, we hypothesize that ICSBP participates in phosphorylation dependent protein-protein interactions, which regulate differentiation-stage-specific myeloid gene expression and are necessary for differentiation progression. We also hypothesize that ICSBP tyrosine phosphorylation induces functional switch from repressor to activator. The following aims will pursue these hypotheses; Aim 1: Determine if ICSBP tyrosine phosphorylation is necessary for progression of myeloid differentiation. Aim 2: Determine if ICSBP function switches from repression to activation during myeloid differentiation. Aim 3: Determine if ICSBP tyrosine phosphorylation is necessary for "tumor suppression" in ICSBP -/- mice. These studies will determine if ICSBP tyrosine phosphorylation is necessary for myeloid differentiation and leukemia suppression, providing a unique model to dissect early events in the evolution of myeloid malignancy.

描述（由申请人提供）：两个观察结果表明干扰素共有序列结合蛋白（ICSBP）对于正常的骨髓分化是必需的。第一个观察结果是 ICSBP -/- 小鼠出现骨髓扩张和免疫功能受损。这表明 ICSBP 对于分化的进展是必需的。第二个观察结果是，ICSBP 表达在人类髓系恶性肿瘤中降低，并且 1CSBP -/- 小鼠会发展为髓系白血病。这表明 ICSBP 在骨髓分化过程中是一种“白血病抑制因子”。我们发现，在晚期骨髓分化过程中，酪氨酸磷酸化的 ICSBP 与 PU.1、干扰素调节因子 1 和 CREB 结合蛋白相互作用。这种相互作用激活编码呼吸爆发氧化酶蛋白 gp91phox 和 p67phoX 的基因。这些结果表明 ICSBP 激活赋予成熟吞噬细胞表型的基因转录。相反，非酪氨酸磷酸化的 ICSBP 抑制未分化骨髓细胞中的 Bcl-XL 表达。这表明 ICSBP 影响早期分化过程中细胞凋亡的启动。因此，在骨髓生成过程中发生的 ICSBP 酪氨酸磷酸化会改变蛋白质-DNA 和蛋白质-蛋白质相互作用。基于这些观察，我们假设 ICSBP 参与磷酸化依赖性蛋白质-蛋白质相互作用，调节分化阶段特异性骨髓基因表达，并且是分化进展所必需的。我们还假设 ICSBP 酪氨酸磷酸化诱导从阻遏蛋白到激活蛋白的功能转换。以下目标将追求这些假设；目标 1：确定 ICSBP 酪氨酸磷酸化对于骨髓分化的进展是否是必需的。目标 2：确定 ICSBP 功能在骨髓分化过程中是否从抑制转变为激活。目标 3：确定 ICSBP 酪氨酸磷酸化对于 ICSBP -/- 小鼠的“肿瘤抑制”是否是必需的。这些研究将确定 ICSBP 酪氨酸磷酸化对于骨髓分化和白血病抑制是否是必需的，从而提供一个独特的模型来剖析骨髓恶性肿瘤进化中的早期事件。