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
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: | School of Biological Sciences > 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: | https://repository.cshl.edu/id/eprint/37123 |
Actions (login required)
 |
Administrator's edit/view item |
