Induction of β-transducin repeat-containing protein by JNK signaling and its role in the activation of NF-κB

Activation of Jun N-kinase (JNK) and NF-kappaB transcription factor are the hallmarks of cellular response to stress. Phosphorylation of NF-kappaB inhibitor (I kappaB) by respective stress-inducible kinases (IKK) is:a key event in NF-kappaB activation. beta -TrCP F-box protein mediates ubiquitination of phosphorylated I kappaB via recruitment of SCFbeta -TrCP-Roc1 E3 ubiquitin Ligase complex. Subsequent proteasome-dependent degradation of I kappaB results in activation of the NF-kappaB pathway, We found that a variety of cellular stress stimuli induce an increase in the steady state levels of beta -TrCP mRNA and protein levels in human cells. Activation of stress-activated protein kinases JNK (and, to a lesser extent, p38) by forced expression of constitutively active mutants of JNKK2 and MKK6 (but not MEK1 or IKK beta) also leads to accumulation of beta -TrCP. Transcription of the beta -TrCP gene is not required for JNK-mediated induction of beta -TrCP. A synergistic effect of stimulation of IKK and JNK on the transcriptional activity of NF-kappaB was observed. The mechanisms of beta -TrCP induction via stress and its role in NF-kappaB activation are discussed.