The role of Krüppel-like Factor 6 in H-rasG12V-induced transformation

TRUCCO L.D.; ANDREOLI V.; BOCCO J.L.

Mendoza

Congreso; XLVIII Reunión Anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2012

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular

The tumor suppressor KLF6 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 cancer. We previously examined the effects of KLF6 on proliferation and transformation of NIH3T3 fibroblasts stably transduced with an inducible H-Ras (G12V). We demonstrate that H-RasG12V induction resulted in increase of KLF6 protein which can be impaired by inhibition of Jun N-terminal Kinases (JNKs). Also, ectopic expression of KLF6 following activation of Ras induce G1 arrest and a decrease in cell proliferation. Furthermore, KLF6 constitutively expressed was able to revert some of the proprieties of the transformed phenotype induced by Ras like loss of density-dependent growth inhibition and the ability to form colonies in soft agar. Here we show that levels of KLF6 transcript is significantly elevated in oncogenic H-Ras-transformed NIH3T3 cells. This KLF6 induction is correlated with increased levels of the cyclin-dependent kinase inhibitor p21 and the suppressor of cellular invasion E-cadherin, with no significant changes of p53 protein levels. Moreover, we used fibroblasts lacking JNK1 or JNK2 to define their roles in KLF6 response to Ras trigger, indicating that both kinases are implicated.