UVB activates ERK1/2 and p38 signaling pathways via reactive oxygen species in cultured keratinocytes

J Invest Dermatol. 1999 May;112(5):751-6. doi: 10.1046/j.1523-1747.1999.00584.x.


We have previously shown that hydrogen peroxide is an important mediator of ultraviolet B induced phosphorylation of the epidermal growth factor receptor in human keratinocytes. Here we demonstrate that physiologic doses of ultraviolet B and hydrogen peroxide stimulate activation of two related but distinct mitogen-activated protein kinase pathways: extracellular regulated kinase 1 and 2 (ERK1/2), as well as p38, the mammalian homolog of HOG1 in yeast which is a major kinase for a recently identified stress-induced signaling pathway. The time-dependent activation of ERK1/2 and p38 are distinct, and ultraviolet B-induced ERK1/2 activation is downregulated more rapidly than p38. Using dihydrorhodamine or Amplex as specific fluorescent dye probes, we show that ultraviolet B-induced peroxides can be inhibited by ascorbic acid. Ascorbic acid strongly blocks ERK1/2 and p38 activation by ultraviolet B and hydrogen peroxide whereas pyrrolidine dithiocarbamate and butyl hydroxyanisole are less effective. Pyrrolidine dithiocarbamate was unable to inhibit ultraviolet B-induced p38 activation. Cell death was increased after ultraviolet B when ERK1/2 activation was attenuated by the specific inhibitor PD098059. The distinct time courses and extents of activation and inhibition of ERK1/2 and p38 indicate that these pathways are separate and regulated independently in keratinocytes. Specific types of reactive oxygen species induced by ultraviolet B as well as selective activation or inhibition of specific phosphatases may mediate these responses in keratinocytes. These findings demonstrate that reactive oxygen species are important multifunctional mediators of ultraviolet B-induced ERK1/2 and p38 signaling transduction pathways and suggest that ERK1/2 may play an important part in protecting keratinocytes from cell death following oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / pharmacology
  • Ascorbic Acid / pharmacology
  • Butylated Hydroxyanisole / pharmacology
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cell Death / drug effects
  • Cell Death / radiation effects
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Dose-Response Relationship, Radiation
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Humans
  • Hydrogen Peroxide / metabolism
  • Hydrogen Peroxide / pharmacology*
  • Intracellular Fluid / drug effects
  • Intracellular Fluid / metabolism
  • Intracellular Fluid / radiation effects
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism
  • Keratinocytes / radiation effects*
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases*
  • Phosphorylation / drug effects
  • Pyrrolidines / pharmacology
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / radiation effects
  • Thiocarbamates / pharmacology
  • Ultraviolet Rays*
  • p38 Mitogen-Activated Protein Kinases


  • Antioxidants
  • Enzyme Inhibitors
  • Flavonoids
  • Pyrrolidines
  • Reactive Oxygen Species
  • Thiocarbamates
  • Butylated Hydroxyanisole
  • pyrrolidine dithiocarbamic acid
  • Hydrogen Peroxide
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Ascorbic Acid
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one