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Control of the autophagy maturation step by the MAPK ERK and p38: lessons from environmental carcinogens

Elisabeth Corcelle1, Nadir Djerbi, Mireille Mari

  • 1INSERM U670, IFR 50, Faculté de Médecine, Avenue de Valombrose, 06107 Nice Cedex 2, France.

Autophagy
|November 15, 2006
PubMed

Insights

Environmental carcinogens disrupt macroautophagy (autophagy) by activating MAPK ERK and p38 pathways. This disruption impairs autophagic maturation, leading to defective autolysosomes and potential disease links.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Macroautophagy (autophagy) is crucial for cellular homeostasis, protein/organelle degradation, and tumor suppression.
  • Dysfunctional autophagy is implicated in various pathologies, including cancer, neurodegeneration, and toxic injury.
  • The precise molecular mechanisms governing autophagy regulation remain incompletely understood.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying autophagy disruption by environmental carcinogens.
  • To identify signaling pathways involved in regulating the autophagy maturation step.
  • To elucidate the role of MAPK pathways in carcinogen-induced autophagic defects.

Main Methods:

  • Utilized environmental carcinogens (Lindane, dichlorodiphenyltrichloroethane, biphenol A, Pentachlorophenol) to disrupt autophagy.
  • Investigated the role of MAPK ERK and p38 signaling pathways using specific activators and inhibitors (MEK1(+), SB203580).
  • Analyzed autophagic flux and autolysosome morphology in response to pathway modulation.

Main Results:

  • Sustained MAPK ERK activation by Lindane or MEK1(+) specifically impairs autophagy at the maturation stage, causing defective autolysosome accumulation.
  • Other xenobiotics activating ERK (dichlorodiphenyltrichloroethane, biphenol A) induced similar defects.
  • Pentachlorophenol, activating both ERK and p38, did not induce autophagic vacuolation defects.
  • Inhibition of p38 MAPK by SB203580 interfered with normal autophagic maturation.

Conclusions:

  • MAPK ERK and p38 pathways play critical roles in regulating autophagy, particularly at the maturation step.
  • Specific activation of MAPK ERK by certain carcinogens disrupts autophagic maturation, leading to autolysosome defects.
  • Understanding these signaling pathways is vital for comprehending autophagy's role in disease and developing therapeutic strategies.

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