Numb-dependent integration of pre-TCR and p53 function in T-cell precursor development

N. M. Martin-Blanco; S. Checquolo; F. Del Gaudio; R. Palermo; G. Franciosa; L. Di Marcotullio; A. Gulino; M. Canelles; I. Screpanti

doi:10.1038/cddis.2014.438

Numb-dependent integration of pre-TCR and p53 function in T-cell precursor development

N. M. Martin-Blanco, S. Checquolo, F. Del Gaudio, R. Palermo, G. Franciosa, L. Di Marcotullio, A. Gulino, M. Canelles, I. Screpanti^*

^*Corresponding author for this work

5 Citations (Scopus)

Abstract

Numb asymmetrically segregates at mitosis to control cell fate choices during development. Numb inheritance specifies progenitor over differentiated cell fates, and, paradoxically, also promotes neuronal differentiation, thus indicating that the role of Numb may change during development. Here we report that Numb nuclear localization is restricted to early thymocyte precursors, whereas timed appearance of pre-T-cell receptor (pre-TCR) and activation of protein kinase Cθ promote phosphorylationdependent Numb nuclear exclusion. Notably, nuclear localization of Numb in early thymocyte precursors favors p53 nuclear stabilization, whereas pre-TCR-dependent Numb nuclear exclusion promotes the p53 downmodulation essential for further differentiation. Accordingly, the persistence of Numb in the nucleus impairs the differentiation and promotes precursor cell death. This study reveals a novel regulatory mechanism for Numb function based on its nucleus-cytosol shuttling, coupling the different roles of Numb with different stages of T-cell development.

Original language	English
Article number	e1472
Journal	Cell Death and Disease
Volume	5
ISSN	2041-4889
DOIs	https://doi.org/10.1038/cddis.2014.438
Publication status	Published - 1 Jan 2014

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title = "Numb-dependent integration of pre-TCR and p53 function in T-cell precursor development",

abstract = "Numb asymmetrically segregates at mitosis to control cell fate choices during development. Numb inheritance specifies progenitor over differentiated cell fates, and, paradoxically, also promotes neuronal differentiation, thus indicating that the role of Numb may change during development. Here we report that Numb nuclear localization is restricted to early thymocyte precursors, whereas timed appearance of pre-T-cell receptor (pre-TCR) and activation of protein kinase Cθ promote phosphorylationdependent Numb nuclear exclusion. Notably, nuclear localization of Numb in early thymocyte precursors favors p53 nuclear stabilization, whereas pre-TCR-dependent Numb nuclear exclusion promotes the p53 downmodulation essential for further differentiation. Accordingly, the persistence of Numb in the nucleus impairs the differentiation and promotes precursor cell death. This study reveals a novel regulatory mechanism for Numb function based on its nucleus-cytosol shuttling, coupling the different roles of Numb with different stages of T-cell development.",

author = "Martin-Blanco, {N. M.} and S. Checquolo and {Del Gaudio}, F. and R. Palermo and G. Franciosa and {Di Marcotullio}, L. and A. Gulino and M. Canelles and I. Screpanti",

year = "2014",

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doi = "10.1038/cddis.2014.438",

language = "English",

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T1 - Numb-dependent integration of pre-TCR and p53 function in T-cell precursor development

AU - Martin-Blanco, N. M.

AU - Checquolo, S.

AU - Del Gaudio, F.

AU - Palermo, R.

AU - Franciosa, G.

AU - Di Marcotullio, L.

AU - Gulino, A.

AU - Canelles, M.

AU - Screpanti, I.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Numb asymmetrically segregates at mitosis to control cell fate choices during development. Numb inheritance specifies progenitor over differentiated cell fates, and, paradoxically, also promotes neuronal differentiation, thus indicating that the role of Numb may change during development. Here we report that Numb nuclear localization is restricted to early thymocyte precursors, whereas timed appearance of pre-T-cell receptor (pre-TCR) and activation of protein kinase Cθ promote phosphorylationdependent Numb nuclear exclusion. Notably, nuclear localization of Numb in early thymocyte precursors favors p53 nuclear stabilization, whereas pre-TCR-dependent Numb nuclear exclusion promotes the p53 downmodulation essential for further differentiation. Accordingly, the persistence of Numb in the nucleus impairs the differentiation and promotes precursor cell death. This study reveals a novel regulatory mechanism for Numb function based on its nucleus-cytosol shuttling, coupling the different roles of Numb with different stages of T-cell development.

AB - Numb asymmetrically segregates at mitosis to control cell fate choices during development. Numb inheritance specifies progenitor over differentiated cell fates, and, paradoxically, also promotes neuronal differentiation, thus indicating that the role of Numb may change during development. Here we report that Numb nuclear localization is restricted to early thymocyte precursors, whereas timed appearance of pre-T-cell receptor (pre-TCR) and activation of protein kinase Cθ promote phosphorylationdependent Numb nuclear exclusion. Notably, nuclear localization of Numb in early thymocyte precursors favors p53 nuclear stabilization, whereas pre-TCR-dependent Numb nuclear exclusion promotes the p53 downmodulation essential for further differentiation. Accordingly, the persistence of Numb in the nucleus impairs the differentiation and promotes precursor cell death. This study reveals a novel regulatory mechanism for Numb function based on its nucleus-cytosol shuttling, coupling the different roles of Numb with different stages of T-cell development.

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DO - 10.1038/cddis.2014.438

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SN - 2041-4889

VL - 5

JO - Cell Death and Disease

JF - Cell Death and Disease

M1 - e1472

ER -

Numb-dependent integration of pre-TCR and p53 function in T-cell precursor development

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