Par-4/THAP1 complex and Notch3 competitively regulated pre-mRNA splicing of CCAR1 and affected inversely the survival of T-cell acute lymphoblastic leukemia cells.
Par-4/THAP1 complex and Notch3 competitively regulated pre-mRNA splicing of CCAR1 and affected inversely the survival of T-cell acute lymphoblastic leukemia cells.
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Par-4/THAP1复合物和Notch3竞争性调节CCAR1的前mRNA剪接并对T细胞急性淋巴细胞白血病细胞的存活产生负向影响
作者：
尽管对儿童t细胞急性淋巴细胞白血病（T-ALL）的强化治疗已经大大改善了临床结果，但T-ALL仍然是儿科肿瘤学的一个重要挑战。在这里，我们报道了前列腺凋亡反应因子-4 （Par-4）和THAP1的协同作用诱导人类T- all细胞系Jurkat细胞、CEM细胞和原代培养的T- all儿童肿瘤T淋巴细胞的细胞周期和凋亡调节因子1 （CCAR1）基因表达和细胞凋亡。par4和THAP1共同激活CCAR1基因的启动子。机制研究表明，par4和THAP1通过其羧基端相互作用形成蛋白复合物，THAP1通过其在氨基端的锌依赖dna结合域与CCAR1启动子结合。par4 /THAP1复合物和Notch3竞争性地结合到CCAR1启动子上，竞争性地调节CCAR1的前mrna选择性剪接，从而导致两种不同的转录本，在T-ALL细胞存活中发挥相反的作用。尽管Notch3通过剪接因子SRp40和SRp55诱导CCAR1 mRNA从全长异构体向较短形式的移位剪接，但Par-4/THAP1复合体强烈拮抗这种诱导作用。我们的发现揭示了par4 / thap1诱导T-ALL细胞凋亡的机制原理，这将有助于开发新的T-ALL治疗策略。
Although the intensification of therapy for children with T-cell acute lymphoblastic leukemia (T-ALL) has substantially improved clinical outcomes, T-ALL remains an important challenge in pediatric oncology. Here, we report that the cooperative synergy between prostate apoptosis response factor-4 (Par-4) and THAP1 induces cell cycle and apoptosis regulator 1 (CCAR1) gene expression and cellular apoptosis in human T-ALL cell line Jurkat cells, CEM cells and primary cultured neoplastic T lymphocytes from children with T-ALL. Par-4 and THAP1 collaborated to activate the promoter of CCAR1 gene. Mechanistic investigations revealed that Par-4 and THAP1 formed a protein complex by the interaction of their carboxyl termini, and THAP1 bound to CCAR1 promoter though its zinc-dependent DNA-binding domain at amino terminus. Par-4/THAP1 complex and Notch3 competitively bound to CCAR1 promoter and competitively modulated alternative pre-mRNA splicing of CCAR1, which resulted in two different transcripts and played an opposite role in T-ALL cell survival. Despite Notch3 induced a shift splicing from the full-length isoform toward a shorter form of CCAR1 mRNA by splicing factor SRp40 and SRp55, Par-4/THAP1 complex strongly antagonized this inductive effect. Our finding revealed a mechanistic rationale for Par-4/THAP1-induced apoptosis in T-ALL cells that would be of benefit to develop a new therapy strategy for T-ALL.
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DOI：
10.1073/pnas.0406882102
发表时间：
2005-05-10
影响因子：
11.1
作者：
Clouaire, T;Roussigne, M;Girard, JP
通讯作者：
Girard, JP
影响因子：
4.8
作者：
Cheema, SK;Mishra, SK;Lopez-Berestein, G
通讯作者：
Lopez-Berestein, G
影响因子：
4.8
作者：
McFie, Pamela J.;Wang, Guo-Li;Roesler, William J.
通讯作者：
Roesler, William J.
影响因子：
5.7
作者：
Zhang, Liyue;Levi, Edi;Rishi, Arun K.
通讯作者：
Rishi, Arun K.
影响因子：
11.2
作者：
Park JT;Shih IeM;Wang TL
通讯作者：
Wang TL