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首页> 外文期刊>Molecular and Cellular Biology >Essential Roles for Ankyrin Repeat and Transactivation Domains in Induction of T-Cell Leukemia by Notch1
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Essential Roles for Ankyrin Repeat and Transactivation Domains in Induction of T-Cell Leukemia by Notch1

机译：锚蛋白重复和反式激活域在Notch1诱导T细胞白血病中的重要作用。

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Notch receptors participate in a conserved signaling pathway that controls the development of diverse tissues and cell types, including lymphoid cells. Signaling is normally initiated through one or more ligand-mediated proteolytic cleavages that permit nuclear translocation of the intracellular portion of the Notch receptor (ICN), which then binds and activates transcription factors of the Su(H)/CBF1 family. Several mammalian Notch receptors are oncogenic when constitutively active, including Notch1, a gene initially identified based on its involvement in a (7;9) chromosomal translocation found in sporadic T-cell lymphoblastic leukemias and lymphomas (T-ALL). To investigate which portions of ICN1 contribute to transformation, we performed a structure-transformation analysis using a robust murine bone marrow reconstitution assay. Both the ankyrin repeat and C-terminal transactivation domains were required for T-cell leukemogenesis, whereas the N-terminal RAM domain and a C-terminal domain that includes a PEST sequence were nonessential. Induction of T-ALL correlated with the transactivation activity of each Notch1 polypeptide when fused to the DNA-binding domain of GAL4, with the exception of polypeptides deleted of the ankyrin repeats, which lacked transforming activity while retaining strong transactivation activity. Transforming polypeptides also demonstrated moderate to strong activation of the Su(H)/CBF1-sensitive HES-1 promoter, while polypeptides with weak or absent activity on this promoter failed to cause leukemia. These experiments define a minimal transforming region for Notch1 in T-cell progenitors and suggest that leukemogenic signaling involves recruitment of transcriptional coactivators to ICN1 nuclear complexes.
机译：Notch受体参与一个保守的信号通路，该信号通路控制着各种组织和细胞类型（包括淋巴样细胞）的发育。信号传导通常通过一个或多个配体介导的蛋白水解裂解来启动，该裂解允许Notch受体（ICN）的细胞内部分发生核易位，然后结合并激活Su（H）/ CBF1家族的转录因子。几种哺乳动物Notch受体具有组成性活性时是致癌的，包括 Notch1 ，该基因最初是根据其参与散发性T细胞淋巴母细胞性白血病和淋巴瘤（T-所有）。为了调查ICN1的哪些部分有助于转化，我们使用健壮的小鼠骨髓重构测定法进行了结构转化分析。锚蛋白重复序列​​和C末端反式激活域都是T细胞白血病发生所必需的，而N末端RAM域和包括PEST序列的C末端域则是不必要的。当融合到GAL4的DNA结合结构域时，T-ALL的诱导与每个Notch1多肽的反式激活相关，但锚蛋白重复序列​​缺失的多肽除外，后者缺乏转化活性，同时又保留了强大的反式激活活性。转化的多肽还显示出对Su（H）/ CBF1敏感的HES-1启动子的中等至强激活，而对该启动子具有弱或缺失活性的多肽未能引起白血病。这些实验定义了T细胞祖细胞中Notch1的最小转化区域，并暗示致白血病信号涉及将转录共激活因子募集到ICN1核复合物中。

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