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Flow Cytometric Analysis of Mitochondrial Reactive Oxygen Species in Murine Hematopoietic Stem and Progenitor Cells and MLL-AF9 Driven Leukemia
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MLK3 is part of a feedback mechanism that regulates different cellular responses to reactive oxygen species

Ho-Sung Lee1, Chae Young Hwang2, Sung-Young Shin3

  • 1Laboratory for Systems Biology and Bio-Inspired Engineering, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.

Science Signaling
|June 5, 2014
PubMed

Insights

Reactive oxygen species (ROS) impact cell growth and death by activating mitogen-activated protein kinase (MAPK) pathways. Mixed lineage kinase 3 (MLK3) controls these responses, with its inhibition promoting cell survival.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Reactive oxygen species (ROS) are crucial signaling molecules affecting cellular processes like proliferation and apoptosis.
  • Mitogen-activated protein kinase (MAPK) pathways, including extracellular signal-regulated kinases (ERKs) and c-Jun N-terminal kinases (JNKs), are activated by ROS.
  • ROS concentration dictates cellular fate, with low levels promoting proliferation and high levels inducing cell death.

Purpose of the Study:

  • To investigate the role of Mixed lineage kinase 3 (MLK3) in mediating cellular responses to varying concentrations of ROS.
  • To elucidate the mechanism by which MLK3 influences MAPK pathway activation (ERK vs. JNK) under oxidative stress.
  • To determine if MLK3 is a critical regulator of cell survival or death in response to ROS.

Main Methods:

  • Utilized cell culture models exposed to varying concentrations of ROS.
  • Assessed MAPK pathway activation through phosphorylation analysis of ERKs and JNKs.
  • Employed mathematical modeling to analyze MAPK network dynamics, focusing on MLK3's role.
  • Investigated the effects of MLK3 inhibition and knockdown on cellular responses to ROS.

Main Results:

  • Low ROS concentrations preferentially activated ERK phosphorylation, while high concentrations activated JNK phosphorylation.
  • MLK3 was identified as a direct activator of JNK and potentially involved in ERK activation, forming a positive feedback loop.
  • Inhibition or knockdown of MLK3 led to increased ERK activation, decreased JNK activation, and enhanced resistance to ROS-induced cell death.

Conclusions:

  • MLK3 is a critical determinant of the balance between ERK and JNK activation in response to ROS.
  • The MLK3-mediated signaling network governs cellular fate decisions under oxidative stress.
  • Targeting MLK3 may offer a therapeutic strategy to enhance cell survival in conditions involving high ROS levels.

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