Rapid histone H3 phosphorylation in response to growth factors, phorbol esters, okadaic acid, and protein synthesis inhibitors

Cell. 1991 May 31;65(5):775-83. doi: 10.1016/0092-8674(91)90385-c.


When quiescent cells are stimulated with growth factors, phorbol esters, okadaic acid, or protein synthesis inhibitors, the early-response genes, which include c-fos and c-jun, are rapidly induced. The earliest growth factor- and phorbol ester-stimulated nuclear signaling events concomitant with proto-oncogene induction are the rapid phosphorylation of two chromatin-associated proteins, pp33 and pp15. We show here that the tumor promoter okadaic acid, which inhibits protein phosphatases 1 and 2A, and the protein synthesis inhibitors anisomycin and cycloheximide also stimulate pp33 and pp15 phosphorylation. Using transcriptional inhibitors, we show that this response is not a consequence of early gene induction. By peptide mapping and microsequencing, chromatin-associated pp15 is identified as histone H3. Upon stimulation, histone H3 is rapidly phosphorylated on serine residues within its highly charged, basic N-terminal domain. Thus, these diverse agents elicit a common early nuclear signal modulating nucleosomal structure or function, potentially contributing to conformational regulation of proto-oncogene induction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amanitins / pharmacology
  • Amino Acid Sequence
  • Animals
  • Anisomycin / pharmacology
  • Cell Line
  • Chromatin / drug effects
  • Chromatin / metabolism
  • Cycloheximide / pharmacology
  • Dactinomycin / pharmacology
  • Ethers, Cyclic / pharmacology*
  • Growth Substances / pharmacology*
  • Histones / metabolism*
  • Mice
  • Mice, Inbred C3H
  • Molecular Sequence Data
  • Nucleosomes / drug effects
  • Nucleosomes / physiology
  • Okadaic Acid
  • Phosphates / metabolism
  • Phosphopeptides / isolation & purification
  • Phosphorylation
  • Protein Synthesis Inhibitors / pharmacology*
  • Proto-Oncogenes / drug effects
  • Tetradecanoylphorbol Acetate / pharmacology*
  • Transcription, Genetic / drug effects


  • Amanitins
  • Chromatin
  • Ethers, Cyclic
  • Growth Substances
  • Histones
  • Nucleosomes
  • Phosphates
  • Phosphopeptides
  • Protein Synthesis Inhibitors
  • Dactinomycin
  • Okadaic Acid
  • Anisomycin
  • Cycloheximide
  • Tetradecanoylphorbol Acetate