Regulation of the gadd45beta promoter by NF-kappaB.
In addition to coordinating immune and inflammatory responses, NF-kappaB/Rel transcription factors control cell survival. The NF-kappaB 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-kappaB, and that this suppression involves the upregulation of gadd45beta/myd118. Induction of gadd45beta by stress and cytokines requires NF-kappaB; however, the regulatory mechanisms underlying this induction are not known. Here, we report that, in HeLa cells, the NF-kappaB subunit RelA is sufficient to activate gadd45beta expression, whereas Rel and p50 are not. Activation of gadd45beta by RelA depends on three kappaB elements at positions -447/-438 (kappaB-1), -426/-417 (kappaB-2), and -377/-368 (kappaB-3) of the gadd45beta promoter. Each of these sites binds to NF-kappaB complexes in vitro, and is required for optimal promoter transactivation. The data establish the direct participation of NF-kappaB in the regulation of Gadd45beta, thereby providing important mechanistic insights into the control of apoptosis by the transcription factor.
Jin
Rongguan
R
The Gwen Knapp Center for Lupus and Immunology Research, and The Ben May Institute for Cancer Research, Committees on Immunology and Cancer Biology, The University of Chicago, Chicago, Illinois 60637, USA.
De Smaele
Enrico
E
Zazzeroni
Francesca
F
Nguyen
Dung U
DU
Papa
Salvatore
S
Jones
Joy
J
Cox
Carrie
C
Gelinas
Celine
C
Franzoso
Guido
G
D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D008025:Ligases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation; D015854:Up-Regulation; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D008025:Ligases; D016328:NF-kappa B; C086470:GADD45B protein, human; D000097642:GADD45 Proteins; C490125:Gadd45b protein, mouse; C028812:guanosine 3',5'-polyphosphate synthetases