TY - JOUR
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.
UR - http://www.scopus.com/inward/record.url?scp=84925810051&partnerID=8YFLogxK
U2 - 10.1038/cddis.2014.438
DO - 10.1038/cddis.2014.438
M3 - Journal article
C2 - 25321479
AN - SCOPUS:84925810051
SN - 2041-4889
VL - 5
JO - Cell Death and Disease
JF - Cell Death and Disease
M1 - e1472
ER -