title: 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.
abstract: 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.
authors: Department of Pediatrics, the First Affiliated Hospital of Nanjing Medical University, Jiangsu, China.
authors: C
authors: C
authors: Lu
authors: Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu, China.
authors: J-Y
authors: JY
authors: Li
authors: Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu, China.
authors: Z
authors: Z
authors: Ge
authors: Department of Pediatrics, the First Affiliated Hospital of Nanjing Medical University, Jiangsu, China.
authors: L
authors: L
authors: Zhang
authors: Department of Pediatrics, the First Affiliated Hospital of Nanjing Medical University, Jiangsu, China.
authors: G-P
authors: GP
authors: Zhou
mesh_terms: D017398:Alternative Splicing; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism*; D001665:Binding Sites; D001667:Binding, Competitive; D018797:Cell Cycle Proteins / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D023061:Gene Order; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D059372:Nucleotide Motifs; D010750:Phosphoproteins / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D012322:RNA Precursors / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000378:metabolism; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000378:metabolism*; D000068103:Serine-Arginine Splicing Factors; D015533:Transcriptional Activation
chemical_list: D051017:Apoptosis Regulatory Proteins; C477529:CCAR1 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; C499374:NOTCH3 protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D000071656:Receptor, Notch3; D051880:Receptors, Notch; C489470:SRSF6 protein, human; C474080:THAP1 protein, human; C101296:prostate apoptosis response-4 protein; D000068103:Serine-Arginine Splicing Factors
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