Stage-specific roles for Zmiz1 in Notch-dependent steps of early T-cell development

Wang, Q., Yan, R., Pinnell, N., McCarter, A. C., Oh, Y., Liu, Y., Sha, C., Garber, N. F., Chen, Y., Wu, Q., Ku, C. J., Tran, I., Serna Alarcon, A., Kuick, R., Engel, J. D., Maillard, I., Cierpicki, T., Chiang, M. Y. (August 2018) Stage-specific roles for Zmiz1 in Notch-dependent steps of early T-cell development. Blood, 132 (12). pp. 1279-1292. ISSN 0006-4971

URL: https://www.ncbi.nlm.nih.gov/pubmed/30076146
DOI: 10.1182/blood-2018-02-835850

Abstract

Notch1 signaling must elevate to high levels in order to drive the proliferation of CD4(-)CD8(-) double-negative (DN) thymocytes and progression to the CD4(+)CD8(+) double-positive (DP) stage through beta-selection. During this critical phase of pre-T cell development, which is also known as the DN-DP transition, it is unclear whether the Notch1 transcriptional complex strengthens its signal output as a discrete unit or through cofactors. We previously showed that the protein inhibitor of activated STAT (PIAS)-like coactivator Zmiz1 is a context-dependent cofactor of Notch1 in T-cell leukemia. We also showed that withdrawal of Zmiz1 generated an early T-lineage progenitor (ETP) defect. Here, we show that this early defect seems inconsistent with loss-of-Notch1 function. In contrast, at the later pre-T cell stage, withdrawal of Zmiz1 impaired the DN-DP transition by inhibiting proliferation, like withdrawal of Notch. In pre-T cells, but not ETPs, Zmiz1 cooperatively regulated Notch1 target genes Hes1, Lef1, and Myc Enforced expression of either activated Notch1 or Myc partially rescued the Zmiz1-deficient DN-DP defect. We identified residues in the tetratricopeptide repeat (TPR) domain of Zmiz1 that bind Notch1. Mutating only a single residue impaired the Zmiz1-Notch1 interaction, Myc induction, the DN-DP transition, and leukemic proliferation. Similar effects were seen using a dominant-negative TPR protein. Our studies identify stage-specific roles of Zmiz1. Zmiz1 is a context-specific cofactor for Notch1 during Notch/Myc-dependent thymocyte proliferation, whether normal or malignant. Finally, we highlight a vulnerability in leukemic cells that originated from a developmentally important Zmiz1-Notch1 interaction that is hijacked during transformation from normal pre-T cells.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > Notch
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells
CSHL Authors:
Communities: Watson School > Publications
Depositing User: Matthew Dunn
Date: 3 August 2018
Date Deposited: 14 Aug 2018 18:58
Last Modified: 12 Aug 2019 15:42
PMCID: PMC6148450
Related URLs:
URI: http://repository.cshl.edu/id/eprint/37123

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