title: A RelA(p65) Thr505 phospho-site mutation reveals an important mechanism regulating NF-κB-dependent liver regeneration and cancer.
abstract: Post-translational modifications of nuclear factor (NF)-κB subunits provide a mechanism to differentially regulate their activity in response to the many stimuli that induce this pathway. However, the physiological significance of these modifications is largely unknown, and it remains unclear if these have a critical role in the normal and pathological functions of NF-κB in vivo. Among these, phosphorylation of the RelA(p65) Thr505 residue has been described as an important regulator of NF-κB activity in cell lines, but its physiological significance was not known. Therefore, to learn more about the role of this pathway in vivo, we generated a knockin mouse with a RelA T505A mutation. Unlike RelA knockout mice, the RelA T505A mice develop normally but exhibit aberrant hepatocyte proliferation following liver partial hepatectomy or damage resulting from carbon tetrachloride (CCl4) treatment. Consistent with these effects, RelA T505A mice exhibit earlier onset of cancer in the N-nitrosodiethylamine model of hepatocellular carcinoma. These data reveal a critical pathway controlling NF-κB function in the liver that acts to suppress the tumour-promoting activities of RelA.
authors: Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
authors: A
authors: A
authors: Moles
authors: Institute for Cell and Molecular Biosciences (ICaMB), Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
authors: J A
authors: JA
authors: Butterworth
authors: Institute for Cell and Molecular Biosciences (ICaMB), Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
authors: A
authors: A
authors: Sanchez
authors: Institute for Cell and Molecular Biosciences (ICaMB), Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
authors: J E
authors: JE
authors: Hunter
authors: Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
authors: J
authors: J
authors: Leslie
authors: Institute for Cell and Molecular Biosciences (ICaMB), Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
authors: H
authors: H
authors: Sellier
authors: Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
authors: D
authors: D
authors: Tiniakos
authors: Bioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
authors: S J
authors: SJ
authors: Cockell
authors: Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
authors: D A
authors: DA
authors: Mann
authors: Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
authors: F
authors: F
authors: Oakley
authors: Institute for Cell and Molecular Biosciences (ICaMB), Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
authors: N D
authors: ND
authors: Perkins
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002251:Carbon Tetrachloride / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D055879:Gene Knock-In Techniques; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008115:Liver Regeneration / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics*; D010766:Phosphorylation / Q000235:genetics; D051996:Transcription Factor RelA / Q000235:genetics*
chemical_list: D016328:NF-kappa B; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D002251:Carbon Tetrachloride