Other
18 Authors
- Tran I,
- Yan R,
- Wang Q,
- Wu Q,
- Garber NF,
- Liu Y,
- Cierpicki T,
- Engel JD,
- Maillard I,
- Serna Alarcon A,
- Kuick R,
- Sha C,
- McCarter AC,
- Ku CJ,
- Chen Y,
- Chiang MY,
- Pinnell N,
- Oh Y
| First Author | Wang Q | Year | 2018 |
| Journal | Blood | Volume | 132 |
| Issue | 12 | Pages | 1279-1292 |
| PubMed ID | 30076146 | Mgi Jnum | J:266278 |
| Mgi Id | MGI:6201964 | Doi | 10.1182/blood-2018-02-835850 |
| Citation | Wang Q, et al. (2018) Stage-specific roles for Zmiz1 in Notch-dependent steps of early T-cell development. Blood 132(12):1279-1292 |
| abstractText | 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-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. |
