Notch3 and the Notch3-upregulated RNA-binding protein HuD regulate Ikaros alternative splicing

Diana Bellavia, Marco Mecarozzi, Antonio F. Campese, Paola Grazioli, Claudio Talora, Luigi Frati, Alberto Gulino, Isabella Screpanti

Research output: Contribution to journalArticle

Abstract

Constitutive activation of the transmembrane receptor, Notch3, and loss of function of the hematopoietic transcription repressor, Ikaros (IK), play direct roles in T-cell differentiation and leukemogenesis that are dependent on pre-T-cell receptor (pre-TCR) signaling. We demonstrate the occurrence of crosstalk between Notch3 and IK that results in transcriptional regulation of the gene encoding the pTα chain of the pre-TCR. We also show that, in the presence of the pre-TCR, constitutive activation of Notch3 in thymocytes causes increased expression of dominantnegative non-DNA-binding IK isoforms, which are able to restrain the IK inhibition of Notch3's transcriptional activation of pTα. This effect appears to be mediated by Notch3's pre-TCR-dependent upregulation of the RNA-binding protein, HuD. Notch3 signaling thus appears to play a critical role in the diminished IK activity described in several lymphoid leukemias. By exerting transcription-activating and transcription-repressing effects on the pTα promoter, Notch3 and IK cooperate in the fine-tuning of pre-TCR expression and function, which has important implications for the regulation of thymocyte differentiation and proliferation.

Original languageEnglish
Pages (from-to)1670-1680
Number of pages11
JournalEMBO Journal
Volume26
Issue number6
DOIs
Publication statusPublished - Mar 21 2007

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Keywords

  • Alternative splicing
  • Ikaros
  • Notch3
  • Pre-TCR
  • T-cell leukemia

ASJC Scopus subject areas

  • Cell Biology
  • Genetics

Cite this

Bellavia, D., Mecarozzi, M., Campese, A. F., Grazioli, P., Talora, C., Frati, L., Gulino, A., & Screpanti, I. (2007). Notch3 and the Notch3-upregulated RNA-binding protein HuD regulate Ikaros alternative splicing. EMBO Journal, 26(6), 1670-1680. https://doi.org/10.1038/sj.emboj.7601626