Myc coordinates transcription and translation to enhance transformation and suppress invasiveness

Abstract

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.

Let‐7a‐regulated translational readthrough of mammalian AGO 1 generates a micro RNA pathway inhibitor

“…Sixteen ribosome profiling data files from U2-OS cells showed strong evidence of translational readthrough (a > 20-fold increase in ribosomal density in the ISR compared to 3 0 UTR; Table EV1). Therefore, we performed 3-nucleotide periodicity for the ribosome profiling data from U2-OS cells (Elkon et al, 2015). The distribution of reads in the ISR was non-uniform, and it was similar to coding sequence with a majority of them in the 0 th frame, which is consistent with translational readthrough of AGO1 ( Fig EV2B).…”

“…Hence, ribosomal footprints found after the canonical stop codon and within the ISR of AGO1 suggest translational readthrough. Therefore, we performed 3-nucleotide periodicity for the ribosome profiling data from U2-OS cells (Elkon et al, 2015). Moreover, we could detect Ago1x by Western blot in these cell lines ( Fig 2G, Appendix Fig S1).…”

“…The ribosome profiling (Ribo-seq) and the mRNA-seq datasets of the U2-OS cell line were taken from the Elkon et al (2015) study (GEO accession no. GSE66927).…”

Diphthamide modification of eEF2 is required for gut tumor‐like hyperplasia induced by oncogenic Ras

“…In addition to the induction of ribosomal genes by Myc, Myc can enhance translation and DNA replication independent of its transactivation function (Cole & Cowling, 2008). Myc enhances translation of ribosomal proteins through mTOR pathway (Elkon et al, 2015). It also increases the rate of translation of cyclin-dependent kinases by promoting their mRNA cap methylation (Cowling & Cole, 2007).…”

MXD/MIZ1 complexes activate transcription of MYC-repressed genes

“…Available RNA-seq data indicate that MIZ1, MYC as well as its antagonists MXD1, MXD2, and MNT are expressed in U2OS cells ( Fig. 1B) (Elkon et al, 2015;Ibarra et al, 2016). To assess whether MXDs are functional and impact expression of MYC repressed genes we analyzed expression of a p21-luc reporter.…”