Interplay Between MEK-ERK Signaling, Cyclin D1, and Cyclin-Dependent Kinase 5 Regulates Cell Cycle Reentry and Apoptosis of Neurons

Mol Biol Cell. 2012 Sep;23(18):3722-30. doi: 10.1091/mbc.E12-02-0125. Epub 2012 Jul 25.

Abstract

In response to neurotoxic signals, postmitotic neurons make attempts to reenter the cell cycle, which results in their death. Although several cell cycle proteins have been implicated in cell cycle-related neuronal apoptosis (CRNA), the molecular mechanisms that underlie this important event are poorly understood. Here, we demonstrate that neurotoxic agents such as β-amyloid peptide cause aberrant activation of mitogen-activated kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) signaling, which promotes the entry of neurons into the cell cycle, resulting in their apoptosis. The MEK-ERK pathway regulates CRNA by elevating the levels of cyclin D1. The increase in cyclin D1 attenuates the activation of cyclin-dependent kinase 5 (cdk5) by its neuronal activator p35. The inhibition of p35-cdk5 activity results in enhanced MEK-ERK signaling, leading to CRNA. These studies highlight how neurotoxic signals reprogram and alter the neuronal signaling machinery to promote their entry into the cell cycle, which eventually leads to neuronal cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Amyloid beta-Peptides / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Apoptosis / physiology*
  • Blotting, Western
  • Butadienes / pharmacology
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cell Cycle / physiology*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cells, Cultured
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism*
  • Cyclin-Dependent Kinase 5 / genetics
  • Cyclin-Dependent Kinase 5 / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • HEK293 Cells
  • Humans
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / genetics
  • MAP Kinase Signaling System / physiology*
  • Microscopy, Fluorescence
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Nitriles / pharmacology
  • PC12 Cells
  • Peptide Fragments / pharmacology
  • RNA Interference
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Adaptor Proteins, Signal Transducing
  • Amyloid beta-Peptides
  • Butadienes
  • CDCA5 protein, human
  • Cell Cycle Proteins
  • Nitriles
  • Peptide Fragments
  • U 0126
  • amyloid beta-protein (1-42)
  • Cyclin D1
  • Cyclin-Dependent Kinase 5
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinases