A new role for the Kruppel-like transcription factor KLF6 as an inhibitor of c-Jun proto-oncoprotein function.
Kruppel-like transcription factors (KLFs) represent one of the most diverse set of regulators in vertebrate organisms. KLF family members are involved in cell proliferation and differentiation control in normal as well as in pathological situations. Here, we demonstrate that KLF6 behaves as a functional antagonist of the c-Jun proto-oncoprotein. Thus, KLF6 overexpression downregulated c-Jun-dependent transcription and a physical interaction between c-Jun and KLF6 was detected. Moreover, cell proliferation induced by c-Jun was significantly decreased by KLF6. The inhibition of c-Jun functions correlates directly with c-Jun protein degradation induced by KLF6. We also show that all KLF6 effects on c-Jun were largely dependent on phorbol ester (TPA/ionomycin) extracellular stimulation, which enhanced KLF6 nuclear translocation and transcriptional activity and modified its phosphorylation status. Our data are consistent with a novel mechanism of KLF6's role as an inhibitor of cell proliferation by counteracting the function of the c-Jun proto-oncoprotein involving enhanced c-Jun degradation by the proteasome-dependent pathway, and further reinforces KLF6 as a potential tumor suppressor gene product.
Slavin
Daniela A
DA
Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI - CONICET). Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
Koritschoner
Nicolás P
NP
Prieto
Claudio C
CC
López-Díaz
Fernando J
FJ
Chatton
Bruno
B
Bocco
José Luis
JL
D000818:Animals; D019556:COS Cells; D002455:Cell Division / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D019169:Jurkat Cells; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D010766:Phosphorylation; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology
C105465:KLF6 protein, human; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D015534:Trans-Activators