Transforming potential of Dbl family proteins correlates with transcription from the cyclin D1 promoter but not with activation of Jun NH2-terminal kinase, p38/Mpk2, serum response factor, or c-Jun

John K. Westwick, Richard J. Lee, Que T. Lambert, Marc Symons, Richard G. Pestell, Channing J. Der, Ian Whitehead

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

The dbl family of oncogenes encodes a large, structurally related, family of growth-regulatory molecules that possess guanine nucleotide exchange factor activity for specific members of the Rho family of Ras- related GTPases. We have evaluated matched sets of weakly and strongly transforming versions of five Dbl family proteins (Lfc, Lsc, Ect2, Dbl, and Dbs) to determine their ability to stimulate signaling pathways that are activated by Rho family proteins. We found that the transforming potential of this panel did not correlate directly with their ability to activate Jun NH2-terminal kinase, p38/Mpk2, serum response factor, or c-Jun. In contrast, transient stimulation of transcription from the cyclin D1 promoter provided a strong correlation with transforming potential, and we found constitutive up- regulation of cyclin D1 protein in Dbl family protein-transformed cells. In addition, we observed that at least two Dbl family members (Lfc and Ect2) induced changes in the actin cytoskeleton and exhibited nuclear signaling profiles that are consistent with a broader range of in vivo substrate utilization than is predicted from their in vitro exchange specificities. In summary, although Dbl family proteins exhibit signaling profiles that are consistent with their in vivo activation of Rho proteins, stimulation of cyclin D1 transcription is the only activity that correlates with transforming potential, thus suggesting that deregulated cell cycle progression may be important for Dbl family protein transformation.

Original languageEnglish (US)
Pages (from-to)16739-16747
Number of pages9
JournalJournal of Biological Chemistry
Volume273
Issue number27
DOIs
StatePublished - Jul 3 1998

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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