KLF6 Tumor Supressor Improves JNK2-Mediated Phosphorylation of c-Jun Oncoprotein Contributing to Apoptosis During DNA-Damage Response.

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

Hotel Sheraton – Iguazú Falls – Province of Misiones

Simposio; Symposium "Gene Expression and RNA Processing" International Centre for Genetic Engineering and Biotechnology (ICGEB); 2011

International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italia and FCEN, Universidad de Buenos Aires

Expression of the transcription factor KLF6 (Krüppel-like Factor 6) is responsive to several environmental stresses as DNA damage, though the underlying mechanisms and how they are integrated with cell biology are largely undeciphered. We have demonstrated that KLF6 promotes proteasomal degradation of c-Jun upon growth signals and tumor promoters, contributing to reduce cell proliferation. The DNA damage response mounted in cells by the p53 tumor suppressor protein is well known, producing cell cycle arrest and apoptosis. In the same context, increased phosphorylation of c-Jun oncoprotein mediated by JNK activities (mainly JNK1) contributes to exit from p53-imposed growth arrest and re-start the cell cycle. Additionally, in cells deficient for JNK2 expression, persistent c-Jun phosphorylation mediated by JNK1 is involved in apoptosis induction following UV radiation. Conversely, in cells lacking JNK1 (jnk1-/-) c-Jun is poorly phosphorylated by JNK2, correlating with a relative resistance of cells to UV-mediated apoptosis. In the present work, results are consistent with a KLF6 role in regulating the function of c-Jun during DNA damage produced by UV radiation. Thus, in the context of cells showing a phenotype relatively resistant to UV-mediated apoptosis (jnk1-/-), expression of KLF6 is associated with enhanced activity of JNK2, leading to a transient increase of c-Jun phosphorylation. In this particular cell context, KLF6 expression is directly associated with increased levels of p53 transcript, induction of p73 gene promoter, caspases-3 /-7 activation, increased Annexin-V cell labeling and changes in ultrastructure cell morphology denoting apoptotic cell death. Results support that KLF6 exerts part of its tumor suppressor activity by exploiting the pro-apoptotic properties of the hyper-phosphorylated form of the c-Jun oncoprotein, which is additionally essential for "switching" the p53 function from cell cycle arrest toward apoptosis.