Description:
Gadd45 alpha, beta, and gamma proteins, also known as growth arrest and DNA damage-inducible factors, have a number of cellular functions, including cell-cycle regulation and propagation of signals produced by a variety of cellular stimuli, maintaining genomic stability and apoptosis. Furthermore, Gadd45 beta has been indicated as a major player in the endogenous NF-kappaB-mediated resistance to apoptosis in a variety of cell lines. NF-? B/Rel transcription factors promote cell survival, and this activity of NF-? B counters programmed cell death (PCD) elicited by the pro-inflammatory cytokine tumor necrosis factor (TNF) alfa. This inhibition of TNFalfa-induced PCD by NF-? B is crucial for sustaining chronic inflammation and tumor progression. In fibroblasts this mechanism involves the inactivation of MKK7, the upstream activator of JNK, by direct binding within the kinase ATP pocket. We have given insights into the structural basis of the Gadd45beta-mediated inactivation of the JNK kinase, MKK7 and provided structural information on Gadd45 beta protein and Gadd45beta-MKK7 complex. Further work is needed to elucidate complex formation and to develop antagonists able to disrupt protein-protein interaction