The interaction between Myc and Miz1 is required to antagonize TGFβ-dependent autocrine signaling during lymphoma formation and maintenance

Jan Van Riggelen, Judith Müller, Tobias Otto, Vincent Beuger, Alper Yetil, Peter S. Choi, Christian Kosan, Tarik Möröy, Dean W. Felsher, Martin Eilers

Research output: Contribution to journalArticle

76 Scopus citations

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 β-2 (TGFβ-2) and TGFβ-3. Upon Myc suppression, TGFβ 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 TGFβ. We demonstrate that, since lymphomas express high levels of TGFβ, they are poised to elicit an autocrine program of senescence upon Myc inactivation, demonstrating that TGFβ is a key factor that establishes oncogene addiction of T-cell lymphomas.

Original languageEnglish (US)
Pages (from-to)1281-1294
Number of pages14
JournalGenes and Development
Volume24
Issue number12
DOIs
StatePublished - Jun 15 2010

Keywords

  • Lymphoma
  • Miz1
  • Myc
  • Senescence
  • T-cell
  • TGFβ

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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  • Cite this

    Van Riggelen, J., Müller, J., Otto, T., Beuger, V., Yetil, A., Choi, P. S., Kosan, C., Möröy, T., Felsher, D. W., & Eilers, M. (2010). The interaction between Myc and Miz1 is required to antagonize TGFβ-dependent autocrine signaling during lymphoma formation and maintenance. Genes and Development, 24(12), 1281-1294. https://doi.org/10.1101/gad.585710