Oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of c-Jun on serines 63 and 73

Nature. 1991 Dec 12;354(6353):494-6. doi: 10.1038/354494a0.

Abstract

Recent advances indicate a link between tumour promoters, transformation, and AP-1 activity. Protein kinase C activation increases AP-1 DNA-binding activity independently of new protein synthesis. AP-1 is also stimulated by transforming oncoproteins and growth factors. These proteins are thought to participate in a signalling cascade affecting the nuclear AP-1 complex composed of the Jun and Fos proteins. Because c-Jun is the most potent transactivator in the AP-1 complex and is elevated in Ha-ras-transformed cells, in which c-Fos is downregulated, we focused on it as a potential target. c-Jun could convert input from an oncogenic signalling cascade into changes in gene expression. Indeed, transformation of rat embryo fibroblasts by c-Jun requires an intact transcriptional activation domain and cooperation with oncogenic Ha-ras. Expression of oncogenic Ha-ras augments transactivation by c-Jun and stimulates its phosphorylation. Here we describe the mapping of the Ha-ras-responsive phosphorylation sites to serines 63 and 73 of c-Jun. Site-directed mutagenesis indicates that phosphorylation of these serines is essential for stimulation of c-Jun activity and for cooperation with Ha-ras in ocogenic transformation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cell Transformation, Neoplastic*
  • Gene Expression Regulation, Neoplastic / physiology*
  • Mice
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Oncogene Protein p21(ras) / physiology*
  • Phosphorylation
  • Proto-Oncogene Proteins c-jun / metabolism
  • Proto-Oncogene Proteins c-jun / physiology*
  • Rats
  • Serine / metabolism
  • Transcription, Genetic
  • Transcriptional Activation

Substances

  • Proto-Oncogene Proteins c-jun
  • Serine
  • Oncogene Protein p21(ras)