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

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

Iguazú, Misiones

Simposio; Symposium: Gene Expression and RNA Processing; 2011

ICGEB - FaCEyN, UBA - IFIBYNE, CONICET - ANPCyT

Expression of the transcription factor KLF6 (Krüppel-like Factor 6) is responsive to environmental stresses as DNA damage, although the underlying mechanisms and how they are integrated with cell biology are undeciphered. We have demonstrated that KLF6 promotes proteasomal degradation of c-Jun upon growth signals and tumor promoters, contributing to reduce proliferation. The DNA damage response mounted by the tumor suppressor p53 is well known, producing cell cycle arrest and apoptosis. Moreover, increased phosphorylation of c-Jun oncoprotein mediated by JNK 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, c-Jun is poorly phosphorylated by JNK2, correlating with a relative resistance of cells to UV-mediated apoptosis. In the present work, results reveal a KLF6 role in regulating the function of c-Jun during DNA damage produced by UV radiation. Thus, in jnk1-/- cells, expression of KLF6 is associated with enhanced activity of JNK2, leading to a transient increase of c-Jun phosphorylation. In this context, KLF6 expression is associated with increased levels of p53 transcript, induction of p73 gene promoter and endogenous protein level, 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.