Myc-dependent apoptosis as a tumor-suppressive mechanism: how do cells discriminate between physiological and oncogenic levels of Myc expression?
Final Report Abstract
The project has focused on understanding the function of one of the one most important human oncoproteins, which drives the genesis of the majority of all human tumors. This protein, termed MYC, was considered to be a transcription factor that exerts its functions via activation and repression of a defined set of target genes. Surprisingly, work in this grant and also by other groups has shown that MYC proteins universally bind to all active promoters in a cell and that the extent of MYC binding to a given promoter parallels promoter activity. This finding, which by now is consensus in the field, has necessitated a major re-evaluation of the models of why MYC proteins are oncogenic factors. By now, MYC proteins are considered to deeply affect the transcription process itself in many ways and may therefore be oncogenic independent od regulation of specific genes. One key aim of the work in our work was to understand why MYC-driven tumors can be recognized by their specific gene expression profiles despite the universal binding to active promoters. We found that the interaction of MYC with MIZ1, a factor that can blunt MYC transcriptional activities, and differences in the affinity of MYC for specific promoters establish this specificity. We also found that only high, oncogenic levels of MYC engage MIZ1, arguing that it may act as a safeguard against deregulated MYC-dependent function. Consistent with this view, we found that engagement of MIZ1 by MYC is required to promote MYC-dependent apoptosis in epithelial cells, which is considered a major factor that protects human beings from MYC-driven tumorigenesis. A major surprise of our work was the observation that MYC-driven apoptosis can also be suppressed by signals that lie within the MYC gene itself. We found that the 3'-UTR of the MYC gene contains a glutamine-responsive element, that couples MYC-driven global transcriptional elongation to the supply of nucleotides, which require glutamine for their synthesis. This challenges the view that current tissue culture and transgenic models correctly portray MYC-driven apoptosis.
Publications
- (2014) Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles. Nature 511: 483-7
Walz S, Lorenzin F, Morton J, Wiese KE, von Eyss B, Herold S, Rycak L, Dumay-Odelot H, Karim S, Bartkuhn M, Roels F, Wustefeld T, Fischer M, Teichmann M, Zender L, Wei CL, Sansom O, Wolf E, Eilers M
(See online at https://doi.org/10.1038/nature13473) - (2015) A MYC-Driven Change in Mitochondrial Dynamics Limits YAP/TAZ Function in Mammary Epithelial Cells and Breast Cancer. Cancer cell 28: 743-757
von Eyss B, Jaenicke LA, Kortlever RM, Royla N, Wiese KE, Letschert S, McDuffus LA, Sauer M, Rosenwald A, Evan GI, Kempa S, Eilers M
(See online at https://doi.org/10.1016/j.ccell.2015.10.013) - (2015) Repression of SRF target genes is critical for Myc-dependent apoptosis of epithelial cells. The EMBO journal 34: 1554-71
Wiese KE, Haikala HM, von Eyss B, Wolf E, Esnault C, Rosenwald A, Treisman R, Klefstrom J, Eilers M
(See online at https://doi.org/10.15252/embj.201490467) - (2016) Different promoter affinities account for specificity in MYC-dependent gene regulation. eLife 5
Lorenzin F, Benary U, Baluapuri A, Walz S, Jung LA, von Eyss B, Kisker C, Wolf J, Eilers M, Wolf E
(See online at https://doi.org/10.7554/eLife.15161.001) - (2016) The Interaction of Myc with Miz1 Defines Medulloblastoma Subgroup Identity. Cancer cell 29: 5-16
Vo BT, Wolf E, Kawauchi D, Gebhardt A, Rehg JE, Finkelstein D, Walz S, Murphy BL, Youn YH, Han YG, Eilers M, Roussel MF
(See online at https://doi.org/10.1016/j.ccell.2015.12.003) - (2017) The MYC mRNA 3'-UTR couples RNA polymerase II function to glutamine and ribonucleotide levels. The EMBO journal 36: 1854-1868
Dejure FR, Royla N, Herold S, Kalb J, Walz S, Ade CP, Mastrobuoni G, Vanselow JT, Schlosser A, Wolf E, Kempa S, Eilers M
(See online at https://doi.org/10.15252/embj.201796662)
