The function of KLF6 in cell death has been reported in different cell types, demonstrating either pro- or anti-apoptotic functions. However the mechanisms involved in these physiologically opposite outcomes are largely unknown. Environmental signals are transduced within cells by MAP kinase-dependent pathways which in turn modify the function of key transcription factors such as c-Jun. We demonstrated that KLF6 interacts with the c-Jun oncoprotein whose function can be regulated by JNK1 or JNK2 to induce differentially proliferation or apoptosis. This work aimed to investigate the role of KLF6 in the context of jnk1-/- and jnk2-/- cells which are resistant or sensitive, respectively, to UV-induced cell death. Endogenous KLF6 protein level was induced after UV radiation in jnk1-/- cells correlating with increased nuclear translocation. Under these conditions, the percentage of living cells marked with Annexin V was substantially increased by KLF6 indicating that cells are committed to UV-induced apoptosis. This effect was abolished upon p38 inhibition and also substantially reverted by a JNK inhibitor. In contrast, KLF6 did not modify the apoptosis induced by JNK1. These data support that KLF6 promotes apoptosis in cells relatively resistant to UV-radiation (jnk1-/-), and also suggest that KLF6 function on cell death is regulated by a combination of both p38 and JNK2 activities.