Format

Send to

Choose Destination
Immunity. 2015 Nov 17;43(5):870-83. doi: 10.1016/j.immuni.2015.10.007. Epub 2015 Oct 27.

The PIAS-like Coactivator Zmiz1 Is a Direct and Selective Cofactor of Notch1 in T Cell Development and Leukemia.

Author information

1
Cancer Biology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA.
2
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
3
Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
4
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
5
Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
6
Department of Pathology, University of Pennsylvania, Philadelphia, PA 19104, USA.
7
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
8
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
9
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: markchia@umich.edu.

Abstract

Pan-NOTCH inhibitors are poorly tolerated in clinical trials because NOTCH signals are crucial for intestinal homeostasis. These inhibitors might also promote cancer because NOTCH can act as a tumor suppressor. We previously reported that the PIAS-like coactivator ZMIZ1 is frequently co-expressed with activated NOTCH1 in T cell acute lymphoblastic leukemia (T-ALL). Here, we show that similar to Notch1, Zmiz1 was important for T cell development and controlled the expression of certain Notch target genes, such as Myc. However, unlike Notch, Zmiz1 had no major role in intestinal homeostasis or myeloid suppression. Deletion of Zmiz1 impaired the initiation and maintenance of Notch-induced T-ALL. Zmiz1 directly interacted with Notch1 via a tetratricopeptide repeat domain at a special class of Notch-regulatory sites. In contrast to the Notch cofactor Maml, which is nonselective, Zmiz1 was selective. Thus, targeting the NOTCH1-ZMIZ1 interaction might combat leukemic growth while avoiding the intolerable toxicities of NOTCH inhibitors.

PMID:
26522984
PMCID:
PMC4654973
DOI:
10.1016/j.immuni.2015.10.007
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center