TY  - JOUR
A1  - Elkon, Ran
A1  - Loayza-Puch, Fabricio
A1  - Korkmaz, Gozde
A1  - Lopes, Rui
A1  - van Breugel, Pieter C
A1  - Bleijerveld, Onno B
A1  - Altelaar, AF Maarten
A1  - Wolf, Elmar
A1  - Lorenzin, Francesca
A1  - Eilers, Martin
A1  - Agami, Reuven
T1  - Myc coordinates transcription and translation to enhance transformation and suppress invasiveness
JF  - EMBO reports
N2  - c‐Myc is one of the major human proto‐oncogenes and is often associated with tumor aggression and poor clinical outcome. Paradoxically, Myc was also reported as a suppressor of cell motility, invasiveness, and metastasis. Among the direct targets of Myc are many components of the protein synthesis machinery whose induction results in an overall increase in protein synthesis that empowers tumor cell growth. At present, it is largely unknown whether beyond the global enhancement of protein synthesis, Myc activation results in translation modulation of specific genes. Here, we measured Myc‐induced global changes in gene expression at the transcription, translation, and protein levels and uncovered extensive transcript‐specific regulation of protein translation. Particularly, we detected a broad coordination between regulation of transcription and translation upon modulation of Myc activity and showed the connection of these responses to mTOR signaling to enhance oncogenic transformation and to the TGFβ pathway to modulate cell migration and invasiveness. Our results elucidate novel facets of Myc‐induced cellular responses and provide a more comprehensive view of the consequences of its activation in cancer cells.
KW  - c‐Myc
KW  - transcriptional responses
KW  - translational regulation
KW  - transcription
KW  - transformation
KW  - metastasis
KW  - cancer
KW  - protein biosynthesis & quality control
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150373
VL  - 16
IS  - 12
ER  - 
TY  - JOUR
A1  - Peter, Stefanie
A1  - Bultinck, Jennyfer
A1  - Myant, Kevin
A1  - Jaenicke, Laura A.
A1  - Walz, Susanne
A1  - Müller, Judith
A1  - Gmachl, Michael
A1  - Treu, Matthias
A1  - Boehmelt, Guido
A1  - Ade, Casten P.
A1  - Schmitz, Werner
A1  - Wiegering, Armin
A1  - Otto, Christoph
A1  - Popov, Nikita
A1  - Sansom, Owen
A1  - Kraut, Norbert
A1  - Eilers, Martin
T1  - H Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase
JF  - EMBO Molecular Medicine
N2  - Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARF-BP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high-throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC-dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC-activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells.
KW  - colorectal cancer
KW  - HUWE1
KW  - MIZ1
KW  - MYC
KW  - ubiquitination
KW  - cancer
KW  - digestive system
KW  - pharmacology
KW  - drug discovery
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-118132
SN  - 1757-4684
VL  - 6
IS  - 12
ER  -