The transcription factor KLF6 is a potential tumor suppressor gene product whose expression level is responsive to external cell stimulation mediated by growth factors, tumor promoters and DNA-damage agents. We demonstrated that this factor induced the degradation of the c-Jun proto-oncoprotein leading to inhibition of cell proliferation. Interestingly, consensus amino acid sequences which are targets for JNK-mediated phosphorylation in c-Jun are conserved in KLF6. However, the biochemical pathway involved in the KLF6 response to external signals and its interaction with c-Jun is still unresolved. We observed that in jnk+/+ cells KLF6 protein level was reduced in the cytoplasm upon ectopic expression of both, JNK1 and JNK2. However, JNK2 expression, but not JNK1, enhanced KLF6 detection in the nucleus. In the context of jnk -/- cells, the protein level of KLF6 obtained was severely impaired by JNK1 activity and in a lesser extent by JNK2, which was essential for translocation of KLF6 from cytoplasm to the nucleus. In conclusion, these results identified the JNK pathway involved in the regulation of KLF6 stability and cell distribution. Maximal activity of JNK1 correlates with reduced KLF6 protein level whereas c-Jun is stabilized. Conversely, JNK2 substantially increased KLF6 in the nucleus becoming available to regulate its target genes while c-Jun-sustained proliferation is reduced.
