The interaction between Myc and Miz1 is required to antagonize TGFbeta-dependent autocrine signaling during lymphoma formation and maintenance.
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.
van Riggelen
Jan
J
Department of Medicine, Division of Oncology, Stanford University, School of Medicine, Stanford, California 94304, USA.
Müller
Judith
J
Otto
Tobias
T
Beuger
Vincent
V
Yetil
Alper
A
Choi
Peter S
PS
Kosan
Christian
C
Möröy
Tarik
T
Felsher
Dean W
DW
Eilers
Martin
M
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
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