UVB-induced COX-2 expression requires histone H3 phosphorylation at Ser10 and Ser28

Oncogene. 2013 Jan 24;32(4):444-52. doi: 10.1038/onc.2012.71. Epub 2012 Mar 5.


Cyclooxygenase-2 (COX-2) is an inducible enzyme that contributes to the generation of chronic inflammation in response to chemical carcinogens and environmental stresses, including ultraviolet B (UVB) irradiation. Although post-translational histone modifications are believed to have an important role in modulating transcriptional regulation of UVB-induced COX-2, the underlying biochemical mechanisms are completely unknown. Here, we show that UVB activates the p38 MAPK/MSK1 kinase cascade to phosphorylate histone H3 at Ser10 and Ser28, contributing to UVB-induced COX-2 expression. UVB has no effect on the global tri-methylation level of histone H3 (H3K4me3, H3K9me3, and H3K27me3). We observed that selected mammalian 14-3-3 proteins bind to UVB-induced phosphorylated histone H3 (Ser10 and Ser28). In particular, 14-3-3ɛ is critical for recruiting MSK1 and Cdk9 to the chromatin and subsequently phosphorylating the C-terminal domain of RNA polymerase II in the cox-2 promoter. We propose that histone H3 phosphorylation at Ser10 and Ser28 serve as critical switches to promote cox-2 gene expression by facilitating the recruitment of MSK1 and Cdk9 to the cox-2 promoter, thereby promoting RNA polymerase II phosphorylation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / genetics
  • 14-3-3 Proteins / metabolism
  • Animals
  • Cell Line
  • Cyclin-Dependent Kinase 9 / genetics
  • Cyclin-Dependent Kinase 9 / metabolism
  • Cyclooxygenase 2 / biosynthesis*
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Enzyme Activation / radiation effects
  • HEK293 Cells
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Methylation
  • Mice
  • Phosphorylation
  • Promoter Regions, Genetic
  • RNA Polymerase II / genetics
  • RNA Polymerase II / metabolism
  • Ribosomal Protein S6 Kinases, 90-kDa / genetics
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism
  • Serine / metabolism
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism
  • Ultraviolet Rays
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • 14-3-3 Proteins
  • Histones
  • Transcription Factor AP-1
  • Serine
  • Cyclooxygenase 2
  • Ribosomal Protein S6 Kinases, 90-kDa
  • mitogen and stress-activated protein kinase 1
  • Cyclin-Dependent Kinase 9
  • p38 Mitogen-Activated Protein Kinases
  • RNA Polymerase II