title: The role of RelA (p65) threonine 505 phosphorylation in the regulation of cell growth, survival, and migration.
abstract: The NF-κB family of transcription factors is a well-established regulator of the immune and inflammatory responses and also plays a key role in other cellular processes, including cell death, proliferation, and migration. Conserved residues in the trans-activation domain of RelA, which can be posttranslationally modified, regulate divergent NF-κB functions in response to different cellular stimuli. Using rela(-/-) mouse embryonic fibroblasts reconstituted with RelA, we find that mutation of the threonine 505 (T505) phospho site to alanine has wide-ranging effects on NF-κB function. These include previously described effects on chemotherapeutic drug-induced apoptosis, as well as new roles for this modification in autophagy, cell proliferation, and migration. This last effect was associated with alterations in the actin cytoskeleton and expression of cellular migration-associated genes such as WAVE3 and α-actinin 4. We also define a new component of cisplatin-induced, RelA T505-dependent apoptosis, involving induction of NOXA gene expression, an effect explained at least in part through induction of the p53 homologue, p73. Therefore, in contrast to other RelA phosphorylation events, which positively regulate NF-κB function, we identified RelA T505 phosphorylation as a negative regulator of its ability to induce diverse cellular processes such as apoptosis, autophagy, proliferation, and migration.
authors: Wellcome Trust Centre for Gene Regulation and Expression, University of Dundee, Dundee DD1 5EH, United Kingdom.
authors: Aichi
authors: A
authors: Msaki
authors: Ana M
authors: AM
authors: Sánchez
authors: Li Fang
authors: LF
authors: Koh
authors: Benjamin
authors: B
authors: Barré
authors: Sonia
authors: S
authors: Rocha
authors: Neil D
authors: ND
authors: Perkins
authors: Renée F
authors: RF
authors: Johnson
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000185:Actinin / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D051379:Mice; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D013912:Threonine / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494812:Bcl2l1 protein, mouse; C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C485623:Wasf3 protein, mouse; D051300:Wiskott-Aldrich Syndrome Protein Family; D051020:bcl-X Protein; D000185:Actinin; D013912:Threonine; D002945:Cisplatin