Altered adhesion features and signal transduction in NRK-49F cells transformed by down-regulation of lysyl oxidase.
Lysyl oxidase (LOX) down-regulation induced an oncogenic phenotype in NRK-49F. This event was accompanied by a constitutive activation of ras oncogene and down-regulation of PDGF beta receptor, among other important phenotypic and molecular modifications. In the present paper we show that ras activation is not accompanied by a constitutive activation of the MAP kinases as expected. Surprisingly, even if MAPK-independent, ras activation was accompanied by a constitutive Ser(63) and Ser(73) phosphorylation of c-jun, a further downstream target of ras. Although rare, this ras alternative pathway has been described. Since ras alone is seldom able to trigger cell transformation and the transformed phenotype showed clearly an abnormal adhesion pattern, we investigated the main molecules involved in cell-cell adhesion. In fact, we found that beta-catenin was up-regulated, escaping the glycogen synthase kinase-3 beta (GSK-3 beta) control, through unclear mechanisms. Its nuclear accumulation was accompanied by an up-regulation of cyclin D1, as classically described in the activation of the Wnt/beta-catenin signal pathway. We believe that the resulting up-regulation of cyclin D1 acted in synergy with ras to induce the cell transformation.
Giampuzzi
Monia
M
Laboratorio di Nefrologia, Istituto G. Gaslini, Largo G. Gaslini, 5, 16147 Genova, Italy.
Oleggini
Roberta
R
Di Donato
Armando
A
D000818:Animals; D002448:Cell Adhesion; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D015536:Down-Regulation; D005347:Fibroblasts / Q000502:physiology; D011905:Genes, ras; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007668:Kidney / Q000166:cytology; D008249:Protein-Lysine 6-Oxidase / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D051176:beta Catenin
C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D019938:Cyclin D1; D008249:Protein-Lysine 6-Oxidase; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3