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 pT alpha 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 dominant-negative non-DNA-binding IK isoforms, which are able to restrain the IK inhibition of Notch3's transcriptional activation of pT alpha. 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 pT alpha 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.

Notch3 and the Notch3-upregulated RNA-binding protein HuD regulate Ikaros alternative splicing / Bellavia, Diana; Marco, Mecarozzi; Campese, Antonio Francesco; Grazioli, Paola; Talora, Claudio; Frati, Luigi; Gulino, Alberto; Screpanti, Isabella. - In: EMBO JOURNAL. - ISSN 0261-4189. - STAMPA. - 26:6(2007), pp. 1670-1680. [10.1038/sj.emboj.7601626]

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

BELLAVIA, Diana;CAMPESE, Antonio Francesco;GRAZIOLI, PAOLA;TALORA, Claudio;FRATI, Luigi;GULINO, Alberto;SCREPANTI, Isabella
2007

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 pT alpha 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 dominant-negative non-DNA-binding IK isoforms, which are able to restrain the IK inhibition of Notch3's transcriptional activation of pT alpha. 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 pT alpha 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.
2007
alternative splicing; ikaros; notch3; pre-tcr; t-cell leukemia
01 Pubblicazione su rivista::01a Articolo in rivista
Notch3 and the Notch3-upregulated RNA-binding protein HuD regulate Ikaros alternative splicing / Bellavia, Diana; Marco, Mecarozzi; Campese, Antonio Francesco; Grazioli, Paola; Talora, Claudio; Frati, Luigi; Gulino, Alberto; Screpanti, Isabella. - In: EMBO JOURNAL. - ISSN 0261-4189. - STAMPA. - 26:6(2007), pp. 1670-1680. [10.1038/sj.emboj.7601626]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/361968
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