title: The interaction between Myc and Miz1 is required to antagonize TGFbeta-dependent autocrine signaling during lymphoma formation and maintenance.
abstract: The Myc protein suppresses the transcription of several cyclin-dependent kinase inhibitors (CKIs) via binding to Miz1; whether this interaction is important for Myc's ability to induce or maintain tumorigenesis is not known. Here we show that the oncogenic potential of a point mutant of Myc (MycV394D) that is selectively deficient in binding to Miz1 is greatly attenuated. Binding of Myc to Miz1 is continuously required to repress CKI expression and inhibit accumulation of trimethylated histone H3 at Lys 9 (H3K9triMe), a hallmark of cellular senescence, in T-cell lymphomas. Lymphomas that arise express high amounts of transforming growth factor beta-2 (TGFbeta-2) and TGFbeta-3. Upon Myc suppression, TGFbeta signaling is required to induce CKI expression and cellular senescence and suppress tumor recurrence. Binding of Myc to Miz1 is required to antagonize growth suppression and induction of senescence by TGFbeta. We demonstrate that, since lymphomas express high levels of TGFbeta, they are poised to elicit an autocrine program of senescence upon Myc inactivation, demonstrating that TGFbeta is a key factor that establishes oncogene addiction of T-cell lymphomas.
authors.affiliation: Department of Medicine, Division of Oncology, Stanford University, School of Medicine, Stanford, California 94304, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: van Riggelen
authors.forename: Judith
authors.initials: J
authors.lastname: Müller
authors.forename: Tobias
authors.initials: T
authors.lastname: Otto
authors.forename: Vincent
authors.initials: V
authors.lastname: Beuger
authors.forename: Alper
authors.initials: A
authors.lastname: Yetil
authors.forename: Peter S
authors.initials: PS
authors.lastname: Choi
authors.forename: Christian
authors.initials: C
authors.lastname: Kosan
authors.forename: Tarik
authors.initials: T
authors.lastname: Möröy
authors.forename: Dean W
authors.initials: DW
authors.lastname: Felsher
authors.forename: Martin
authors.initials: M
authors.lastname: Eilers
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D004318:Doxycycline / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D016399:Lymphoma, T-Cell / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism*; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
chemical_list: C489428:Myc protein, mouse; D009687:Nuclear Proteins; D050828:Protein Inhibitors of Activated STAT; D016271:Proto-Oncogene Proteins c-myc; D016212:Transforming Growth Factor beta; C485521:Miz1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D004318:Doxycycline