Regulation of the gadd45� Promoter by NF-?B

Jin, Rongguan; De Smaele, Enrico; Zazzeroni, Francesca; Nguyen, Dung U.; Papa, Salvatore; Jones, Joy; Cox, Carrie; Gelinas, Celine; Franzoso, Guido
July 2002
DNA & Cell Biology;Jul2002, Vol. 21 Issue 7, p491
Academic Journal
In addition to coordinating immune and inflammatory responses, NF-?B/Rel transcription factors control cell survival. The NF-?B antiapoptotic function is crucial to oncogenesis, cancer chemoresistance, and to antagonize tumor necrosis factor (TNF) receptor-induced killing. Recently, we have shown that the suppression of the c-Jun-N-terminal kinase (JNK) cascade is a pivotal protective mechanism by NF-?B, and that this suppression involves the upregulation of gadd45�/myd118. Induction of gadd45� by stress and cytokines requires NF-?B; however, the regulatory mechanisms underlying this induction are not known. Here, we report that, in HeLa cells, the NF-?B subunit RelA is sufficient to activate gadd45� expression, whereas Rel and p50 are not. Activation of gadd45� by RelA depends on three ?B elements at positions -447/-438 (?B-1), -426/-417 (?B-2), and -377/-368 (?B-3) of the gadd45� promoter. Each of these sites binds to NF-?B complexes in vitro, and is required for optimal promoter transactivation. The data establish the direct participation of NF-?B in the regulation of Gadd45�, thereby providing important mechanistic insights into the control of apoptosis by the transcription factor.


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