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

Oncogene. 2013 Dec 12;32(50):5602-13. doi: 10.1038/onc.2013.349. Epub 2013 Aug 26.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Apoptosis
  • Apoptosis Regulatory Proteins / genetics*
  • Apoptosis Regulatory Proteins / metabolism*
  • Binding Sites
  • Binding, Competitive
  • Cell Cycle Proteins / genetics*
  • Cell Survival / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation, Leukemic
  • Gene Order
  • Humans
  • Multiprotein Complexes / metabolism
  • Nuclear Proteins / metabolism*
  • Nucleotide Motifs
  • Phosphoproteins / metabolism
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • RNA Precursors / genetics*
  • RNA Splicing / genetics*
  • RNA-Binding Proteins / metabolism
  • Receptor, Notch3
  • Receptors, Notch / metabolism*
  • Serine-Arginine Splicing Factors
  • Transcriptional Activation

Substances

  • Apoptosis Regulatory Proteins
  • CCAR1 protein, human
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Multiprotein Complexes
  • NOTCH3 protein, human
  • Nuclear Proteins
  • Phosphoproteins
  • RNA Precursors
  • RNA-Binding Proteins
  • Receptor, Notch3
  • Receptors, Notch
  • SRSF6 protein, human
  • THAP1 protein, human
  • prostate apoptosis response-4 protein
  • Serine-Arginine Splicing Factors