KLF6 function involved in c-Jun phosphorylation by JNK2 and its effects in apoptotic resistant cells.

ANDREOLI V.; DIRING J.; CHATTON B.; BOCCO J.L.

San Miguel de Tucumán, Argentina

Congreso; XLV Reunión Anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular.; 2009

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular

KLF6 is a potential tumor suppressor gene product whose expression level responses to growth factors, tumor promoters and DNA-damage. We demonstrated that this transcription factor interacts with the c-Jun promoting its degradation by proteasome. JNKs kinases are the main regulators of c-Jun activity and stability. In the event of DNA damage signaling, JNKs also promote apoptosis involving sustained phosphorylation of c-Jun. Interestingly, expression of KLF6 improves JNK2 activity leading to a transient increase of c-Jun phosphorylation in cells lacking JNK1 activity, correlating with KLF6 nuclear translocation. Under these conditions, apoptotic rate was induced after UV-radiation in jnk1-/- cells, which were initially relative resistant. How can apoptosis be triggered? It is well known that p53 can protect cells from death generating cell cycle arrest by p21 transactivation allowing DNA repair. However, if damage is extensive, p53 stimulates apoptosis through its pro-apoptotic target genes, eg. PUMA and NOXA. Abrogation of cell cycle arrest by phosphorylated c-Jun is essential to switch to the apoptotic program. We observed that over-expression of KLF6 after UV-radiation increases the p53mRNA level in jnk1-/- cells, though its target genes were not induced. In addition, KLF6 is also able to increase the p73 promoter activity whose product is essential for apoptosis in these cells.