title: BRCA1 affects protein phosphatase 6 signalling through its interaction with ANKRD28.
abstract: The tumour suppressor BRCA1 (breast and ovarian cancer-susceptibility gene 1) is implicated in several nuclear processes including DNA repair, transcription regulation and chromatin remodelling. BRCA1 also has some cytoplasmic functions including a pro-apoptotic activity. We identified ANKRD28 (ankyrin repeat domain 28) as a novel BRCA1-interacting protein in a yeast two-hybrid screen and confirmed this interaction by reciprocal immunoprecipitations of the two overexpressed proteins. Endogenous interaction between BRCA1 and ANKRD28 was also observed by co-immunoprecipitation and located in the cytoplasm by proximity ligation assay. The main site of interaction of ANKRD28 on BRCA1 is located in its intrinsically disordered scaffold central region. Whereas ANKRD28 silencing results in a destabilization of IκBε (inhibitor of nuclear factor κBε) through its activation of PP6 (protein phosphatase 6) co-regulator upon TNFα (tumour necrosis factor α) stimulation, BRCA1 overexpression stabilizes IκBε. A truncated form of BRCA1 that does not interact with ANKRD28 has no such effect. Our findings suggest that BRCA1 is a novel modulator of PP6 signalling via its interaction with ANKRD28. This new cytoplasmic process might participate in BRCA1 tumour-suppressor function.
authors.affiliation: Université Lyon I, 28 Rue Laennec, F-69008 Lyon, France INSERM U1052, CRCL, Centre de Recherche en Cancérologie de Lyon, 28 Rue Laennec, F-69008 Lyon, France CNRS UMR5286, CRCL, Centre de Recherche en Cancérologie de Lyon, 28 Rue Laennec, F-69008 Lyon, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Vincent
authors.affiliation: Université Lyon I, 28 Rue Laennec, F-69008 Lyon, France INSERM U1052, CRCL, Centre de Recherche en Cancérologie de Lyon, 28 Rue Laennec, F-69008 Lyon, France CNRS UMR5286, CRCL, Centre de Recherche en Cancérologie de Lyon, 28 Rue Laennec, F-69008 Lyon, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Berthel
authors.affiliation: Université Lyon I, 28 Rue Laennec, F-69008 Lyon, France INSERM U1052, CRCL, Centre de Recherche en Cancérologie de Lyon, 28 Rue Laennec, F-69008 Lyon, France CNRS UMR5286, CRCL, Centre de Recherche en Cancérologie de Lyon, 28 Rue Laennec, F-69008 Lyon, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Dacheux
authors.affiliation: Université Lyon I, 28 Rue Laennec, F-69008 Lyon, France INSERM U1052, CRCL, Centre de Recherche en Cancérologie de Lyon, 28 Rue Laennec, F-69008 Lyon, France CNRS UMR5286, CRCL, Centre de Recherche en Cancérologie de Lyon, 28 Rue Laennec, F-69008 Lyon, France.
authors.forename: Clémence
authors.initials: C
authors.lastname: Magnard
authors.affiliation: Université Lyon I, 28 Rue Laennec, F-69008 Lyon, France INSERM U1052, CRCL, Centre de Recherche en Cancérologie de Lyon, 28 Rue Laennec, F-69008 Lyon, France CNRS UMR5286, CRCL, Centre de Recherche en Cancérologie de Lyon, 28 Rue Laennec, F-69008 Lyon, France nicole.dalla-venezia@lyon.unicancer.fr.
authors.forename: Nicole L Dalla
authors.initials: NL
authors.lastname: Venezia
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C514564:ANKRD28 protein, human; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; C105627:NFKBIE protein, human; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D010749:Phosphoprotein Phosphatases; C572633:protein phosphatase-6 SAPSP1 subunit, human
keywords: ANKRD28; BRCA1; cell surveillance; cytoplasmic signalling; protein interaction; protein phosphatase 6