V-raf confers CSF-1 independent growth to a macrophage cell line and leads to immediate early gene expression without MAP-Kinase activation

D. Buscher, P. Dello Sbarba, R. A. Hipskind, U. R. Rapp, E. R. Stanley, M. Baccarini

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Abstract

The BAC-1.2F5 macrophage cell line depends on CSF-1 for proliferation and survival. Phosphorylation and activation of the RAF-1 kinase are among the early events in CSF-1 signal transduction. To characterize the role of RAF-1 in CSF-1-induced proliferation, we overexpressed oncogenically activated RAF-1, cellular RAF-1 and RAF-1 kinase-defective mutant proteins in BAC-1.2F5 cells. We were unable to establish stable cell lines expressing either kinase-negative or full length RAF-1 proteins, implying that expression of these molecules is not tolerated in BAC-1.2F5 cells. Oncogenically activated RAF-1 induces CSF-1-independent growth in the absence of autocrine growth factor production. Autonomous growth is not associated with dedifferentiation, since v-raf-expressing macrophages perform the same immunological functions as control cells. Intriguingly, autonomous growth correlates with the suppression of CSF-1-mediated MAP-Kinase activation and with the low constitutive expression of a number of CSF-1-inducible genes, including fos, jun, ets2, and myc, but also the genes for the inflammatory cytokines TNFα and IL-1β. Many of these genes have AP-1 binding sites in their promoters, and the v-raf-expressing cells contain constitutive AP-1 binding activity. These data indicate that RAF-1, but not MAP-Kinase, is a key component in CSF-1 mitogenic signal transduction, and are consistent with a working hypothesis in which RAF-1 mediates transcriptional activation of genes via AP-1.

Original languageEnglish (US)
Pages (from-to)3323-3332
Number of pages10
JournalOncogene
Volume8
Issue number12
Publication statusPublished - Jan 1 1993

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ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Buscher, D., Dello Sbarba, P., Hipskind, R. A., Rapp, U. R., Stanley, E. R., & Baccarini, M. (1993). V-raf confers CSF-1 independent growth to a macrophage cell line and leads to immediate early gene expression without MAP-Kinase activation. Oncogene, 8(12), 3323-3332.