title: The PIAS-like Coactivator Zmiz1 Is a Direct and Selective Cofactor of Notch1 in T Cell Development and Leukemia.
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.
authors.affiliation: Cancer Biology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Pinnell
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Ran
authors.initials: R
authors.lastname: Yan
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Hyo Je
authors.initials: HJ
authors.lastname: Cho
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: Keeley
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Murai
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Amparo Serna
authors.initials: AS
authors.lastname: Alarcon
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Qin
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Rork
authors.initials: R
authors.lastname: Kuick
authors.affiliation: Department of Pathology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Kojo S J
authors.initials: KS
authors.lastname: Elenitoba-Johnson
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Maillard
authors.affiliation: 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.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Samuelson
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Cierpicki
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: markchia@umich.edu.
authors.forename: Mark Y
authors.initials: MY
authors.lastname: Chiang
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C497761:NOTCH1 protein, human; D050828:Protein Inhibitors of Activated STAT; D051881:Receptor, Notch1; D014157:Transcription Factors; C480599:ZMIZ1 protein, human