MYC is downregulated by a mitochondrial checkpoint mechanism.

Xiaonan Zhang,Jing Guo,Arjan Mofers,Padraig D'Arcy,Stig Linder,Maria Hägg Olofsson,Per Hydbring

doi:10.18632/oncotarget.21653

Abstract

The MYC proto-oncogene serves as a rheostat coupling mitogenic signaling with the activation of genes regulating growth, metabolism and mitochondrial biogenesis. Here we describe a novel link between mitochondria and MYC levels. Perturbation of mitochondrial function using a number of conventional and novel inhibitors resulted in the decreased expression of MYC mRNA. This decrease in MYC mRNA occurred concomitantly with an increase in the levels of tumor-suppressive miRNAs such as members of the let-7 family and miR-34a-5p. Knockdown of let-7 family or miR-34a-5p could partially restore MYC levels following mitochondria damage. We also identified let-7-dependent downregulation of the MYC mRNA chaperone, CRD-BP (coding region determinant-binding protein) as an additional control following mitochondria damage. Our data demonstrates the existence of a homeostasis mechanism whereby mitochondrial function controls MYC expression.

Highlights

The cell cycle is a finely orchestrated event dependent on the sequential activation of genes regulating cell growth and metabolism
A curious observation from our initial findings was the down-regulation of cytochrome c oxidase subunit 1 (COX-I) protein levels that occurred concomitantly with a reduction in mitochondrial oxidative phosphorylation (OXPHOS) capacity following exposure to VLX600 [31]
In our present investigation we identify the existence of a mitochondrial retrograde signaling mechanism whereby perturbation of mitochondrial function leads to a concomitant down-regulation of MYC expression, linking MYC-regulated cell proliferation to mitochondrial integrity

Summary

Introduction

The cell cycle is a finely orchestrated event dependent on the sequential activation of genes regulating cell growth and metabolism. The proto-oncogene c-MYC (referred to as MYC) represents a master regulator via integration of external mitogenic signaling with the activation of genes required for cell cycle progression [1]. Genes encoding proteins involved in cell growth, metabolism, ribosome biogenesis, protein synthesis and mitochondrial function have all be defined as potential MYC targets. In spite of such a broad range of potential targets, the MYC protein is surprisingly a relatively weak transcriptional activator and is presumed to function as a general enhancer of transcription [3, 4]

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Results

Conclusion