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 phosphorylation-dependent 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.
authors.affiliation: Department of Molecular Medicine, Sapienza University, 00161 Rome, Italy.
authors.forename: N M
authors.initials: NM
authors.lastname: Martin-Blanco
authors.affiliation: Department of Medico-Surgical Sciences and Biotechnology, Sapienza University, Latina 04100, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Checquolo
authors.affiliation: Department of Molecular Medicine, Sapienza University, 00161 Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Del Gaudio
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome 00161, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Palermo
authors.affiliation: Department of Molecular Medicine, Sapienza University, 00161 Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Franciosa
authors.affiliation: Department of Molecular Medicine, Sapienza University, 00161 Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Di Marcotullio
authors.affiliation: 1] Department of Molecular Medicine, Sapienza University, 00161 Rome, Italy [2] Neuromed Institute, Pozzilli 86007, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Gulino
authors.affiliation: Institute of Parasitology and Biomedicine 'Lopez Neyra', Spanish National Research Council, Granada 18100, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Canelles
authors.affiliation: 1] Department of Molecular Medicine, Sapienza University, 00161 Rome, Italy [2] Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome 00161, Italy [3] Institut Pasteur-Foundation Cenci Bolognetti, Sapienza University, Rome 00161, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Screpanti
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D016923:Cell Death; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010766:Phosphorylation; D054504:Precursor Cells, T-Lymphoid / Q000166:cytology* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D000074121:Protein Kinase C-theta; D055550:Protein Stability; D059748:Proteolysis; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C106293:Numb protein, mouse; D011948:Receptors, Antigen, T-Cell; D016159:Tumor Suppressor Protein p53; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D046988:Proteasome Endopeptidase Complex