Journal Article

Rat mammary carcinogenesis induced by <i>in situ</i> expression of constitutive Raf kinase activity is prevented by tethering Raf to the plasma membrane

Daniel R. McFarlin and Michael N. Gould

in Carcinogenesis

Volume 24, issue 6, pages 1149-1153
Published in print June 2003 | ISSN: 0143-3334
Published online June 2003 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgg045
Rat mammary carcinogenesis induced by in situ expression of constitutive Raf kinase activity is prevented by tethering Raf to the plasma membrane

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Mammary carcinogenesis induced through expression of activated Raf was investigated using a model in which retroviral vectors were infused into the central ducts of rat mammary glands. This model allows efficient expression of experimental proteins in a small fraction of endogenous mammary epithelial cells in situ. We previously reported that Raf is the dominant oncogenic signaling pathway from activated Ras in rat mammary glands. We show here that mammary gland carcinogenesis is rapidly induced by the expression of c-Raf-1 kinase that is activated by N-terminal truncation (Δ-Raf). Interestingly, targeting Raf to the plasma membrane via C-terminal fusion with Ras membrane localization signals (Raf-Caax) induces Raf kinase activity that transforms 3T3 cells more frequently than Δ-Raf, yet in situ expression of Raf-Caax does not induce mammary carcinomas. To investigate these contrasting results and begin elucidating the mechanisms of Raf-induced mammary carcinogenesis, we combined both activating mutations (N-terminal truncation and C-terminal membrane localization motifs) in one Raf construct (Δ-Raf-Caax). While Δ-Raf-Caax transforms 3T3 cells more efficiently than Δ-Raf or Raf-Caax, in situ expression of Δ-Raf-Caax does not induce carcinomas in vivo, demonstrating that lipid modification on the C-terminus of Δ-Raf negates its oncogenic potential in rat mammary gland.

Journal Article.  3828 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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