CIBICI   14215
CENTRO DE INVESTIGACION EN BIOQUIMICA CLINICA E INMUNOLOGIA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Krüppel-like Factor 6 induction controls cell transformation upon activation of oncogenic Ras
Autor/es:
TRUCCO L.D.; ANDREOLI V.; BOCCO J.L.
Lugar:
Bariloche, Rio Negro – ARGENTINA
Reunión:
Congreso; The Second South American Symposium in Signal transduction and Molecular Medicine; 2012
Institución organizadora:
National Institute of Health, USA and Universidad de Buenos Aires
Resumen:
The KLF6 tumor suppressor is a member of the Krüppel-like transcription factors family which have diverse roles in cellular differentiation, development, proliferation, signal transduction and apoptosis. KLF6 is ubiquitously expressed and was shown to be inactivated in many types of human malignancies. In this work, the role KLF6 was investigated in the context of the oncogenic pathway triggered by activation of Ras. NIH3T3 fibroblasts were stably transduced for expression of a constitutive activated H-Ras (G12V) mutant whose expression is controlled by a tetracycline-inducible promoter. Induction of H-RasG12V leads to a progressive increase of KLF6 mRNA and protein levels which were impaired by inhibition of Jun N-terminal Kinases (JNKs). Additionally, over expression of KLF6 decreased the cell proliferation sustained by Ras induction, correlating with a G1 cell cycle arrest. Interestingly, levels of the cyclin-dependent kinase inhibitor p21 and the adhesion protein E-cadherin were significantly elevated after ectopic expression of KLF6 in Ras-transformed NIH3T3 cells. However, no significant changes were detected in the levels of p53. Stable expression of KLF6 caused morphological reversion, reduced saturation density and lesser colonies in soft agar of cells expressing constitutively H-RasG12V. Moreover, using mouse fibroblasts deficient in either JNK1 or JNK2, we determine that both kinases are implicated in the KLF6 response to Ras-mediated oncogenesis and that re-expression of the lacking kinase restores the protein levels of KLF6 in each cell line transduced with H-RasG12V. These results are consistent with the ability of KLF6 to impair cellular transformation following activation of oncogenic Ras and that JNK activities contribute to sustain the KLF6 expression.