ROS Inhibits Cell Growth by Regulating 4EBP and S6K, Independent of TOR, during Development

Dev Cell. 2019 May 6;49(3):473-489.e9. doi: 10.1016/j.devcel.2019.04.008.

Abstract

Reactive oxygen species (ROS), despite having damaging roles, serve as signaling molecules regulating diverse biological and physiological processes. Employing in vivo genetic studies in Drosophila, we show that besides causing G1-S arrest by activation of Dacapo, ROS can simultaneously inhibit cell growth by regulating the expression of 4EBP and S6K. This is achieved by triggering a signaling cascade that includes Ask1, JNK, and FOXO independent of the Tsc-TOR growth regulatory pathway. Qualitative and quantitative differences in the types of ROS molecules generated dictate whether cells undergo G1-S arrest only or experience blocks in both cell proliferation and growth. Importantly, during normal development, this signaling cascade is triggered by ecdysone in late larval fat body cells to restrict their growth prior to pupation by antagonizing insulin signaling. The present work reveals an unexpected role of ROS in systemic control of growth in response to steroid hormone signaling to establish organismal size.

Keywords: 4EBP; Drosophila; JNK; ROS; S6K; TOR; ecdysone; growth; mitochondria; organismal size.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle
  • Cell Cycle Checkpoints / physiology
  • Cell Proliferation / physiology
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / cytology
  • Drosophila melanogaster / metabolism
  • Ecdysone / metabolism
  • Forkhead Transcription Factors / metabolism
  • Insulin / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Larva / metabolism
  • MAP Kinase Kinase Kinases / metabolism
  • MAP Kinase Signaling System
  • Peptide Initiation Factors / metabolism*
  • Reactive Oxygen Species / metabolism*
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism*
  • Signal Transduction / physiology
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Drosophila Proteins
  • FOXO protein, Drosophila
  • Forkhead Transcription Factors
  • Insulin
  • Intracellular Signaling Peptides and Proteins
  • Peptide Initiation Factors
  • Reactive Oxygen Species
  • Thor protein, Drosophila
  • Ecdysone
  • Receptor Protein-Tyrosine Kinases
  • tor protein, Drosophila
  • Ribosomal Protein S6 Kinases, 70-kDa
  • TOR Serine-Threonine Kinases
  • ribosomal protein S6 kinase, 70kD, polypeptide 2
  • ASK1 protein, Drosophila
  • MAP Kinase Kinase Kinases