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

59 Citations (Scopus)

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

Fingerprint

RNA-Binding Proteins
Alternative Splicing
T-Cell Antigen Receptor
Transcription
Chemical activation
Thymocytes
Lymphoid Leukemia
Gene encoding
T-cells
Crosstalk
Transcriptional Activation
Cell Differentiation
Protein Isoforms
Up-Regulation
Tuning
T-Lymphocytes
Genes

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., ... 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

Notch3 and the Notch3-upregulated RNA-binding protein HuD regulate Ikaros alternative splicing. / Bellavia, Diana; Mecarozzi, Marco; Campese, Antonio F.; Grazioli, Paola; Talora, Claudio; Frati, Luigi; Gulino, Alberto; Screpanti, Isabella.

In: EMBO Journal, Vol. 26, No. 6, 21.03.2007, p. 1670-1680.

Research output: Contribution to journalArticle

Bellavia, D, Mecarozzi, M, Campese, AF, 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, vol. 26, no. 6, pp. 1670-1680. https://doi.org/10.1038/sj.emboj.7601626
Bellavia, Diana ; Mecarozzi, Marco ; Campese, Antonio F. ; Grazioli, Paola ; Talora, Claudio ; Frati, Luigi ; Gulino, Alberto ; Screpanti, Isabella. / Notch3 and the Notch3-upregulated RNA-binding protein HuD regulate Ikaros alternative splicing. In: EMBO Journal. 2007 ; Vol. 26, No. 6. pp. 1670-1680.
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