Identification of a conserved negative regulatory sequence that influences the leukemogenic activity of NOTCH1
Identification of a conserved negative regulatory sequence that influences the leukemogenic activity of NOTCH1
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DOI：
10.1128/mcb.02478-05
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发表时间：
2006-08-01
影响因子：
5.3
通讯作者：
Aster, Jon C.
中科院分区：
文献类型：
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作者：
Chiang, Mark Y.;Xu, Mina L.;Aster, Jon C.
NOTCH1是一种大型I型跨膜受体，通过依赖于受调节的蛋白水解的信号通路调节正常t细胞的发育。配体结合诱导NOTCH1的蛋白水解裂解，释放其胞内结构域（ICN1），该结构域易位到细胞核，并通过与另外两种蛋白质（dna结合因子CSL和Mastermind-like （MAML）共激活因子）形成短寿命核复合体激活靶基因。最近的研究表明，人类T-ALL通常与c端NOTCH1截断有关，该截断均匀地去除位于残基2524和2556之间的序列。该区域包括高度保守的序列WSSSSP (S4)，根据其氨基酸含量，它可能是调节丝氨酸磷酸化事件的一个位点。我们发现S4序列的突变导致ICN1的低磷酸化；NOTCH1信号增加；以及含有ICN1、CSL和MAML1的配合物的稳定性。与这些体外研究一致，在小鼠骨髓移植模型中，WSSSSP序列的突变将非白血病弱功能获得性NOTCH1等位基因转化为引起侵袭性t - all的等位基因。这些研究表明，S4是一个重要的负调控序列，S4的缺失可能与人类T-ALL的发生有关。
NOTCH1 is a large type I transmembrane receptor that regulates normal T-cell development via a signaling pathway that relies on regulated proteolysis. Ligand binding induces proteolytic cleavages in NOTCH1 that release its intracellular domain (ICN1), which translocates to the nucleus and activates target genes by forming a short-lived nuclear complex with two other proteins, the DNA-binding factor CSL and a Mastermind-like (MAML) coactivator. Recent work has shown that human T-ALL is frequently associated with C-terminal NOTCH1 truncations, which uniformly remove sequences lying between residues 2524 and 2556. This region includes the highly conserved sequence WSSSSP (S4), which based on its amino acid content appeared to be a likely site for regulatory serine phosphorylation events. We show here that the mutation of the S4 sequence leads to hypophosphorylation of ICN1; increased NOTCH1 signaling; and the stabilization of complexes containing ICN1, CSL, and MAML1. Consistent with these in vitro studies, mutation of the WSSSSP sequence converts nonleukemogenic weak gain-of-function NOTCH1 alleles into alleles that cause aggressive T-ALLs in a murine bone marrow transplant model. These studies indicate that S4 is an important negative regulatory sequence and that the deletion of S4 likely contributes to the development of human T-ALL.