title: Notch3 and canonical NF-kappaB signaling pathways cooperatively regulate Foxp3 transcription.
abstract: Notch3 overexpression has been previously shown to positively regulate the generation and function of naturally occurring regulatory T cells and the expression of Foxp3, in cooperation with the pTα/pre-TCR pathway. In this study, we show that Notch3 triggers the trans activation of Foxp3 promoter depending on the T cell developmental stage. Moreover, we discovered a novel CSL/NF-κB overlapping binding site within the Foxp3 promoter, and we demonstrate that the activation of NF-κB, mainly represented by p65-dependent canonical pathway, plays a positive role in Notch3-dependent regulation of Foxp3 transcription. Accordingly, the deletion of protein kinase C, which mediates canonical NF-κB activation, markedly reduces regulatory T cell number and per cell Foxp3 expression in transgenic mice with a constitutive activation of Notch3 signaling. Collectively, our data indicate that the cooperation among Notch3, protein kinase C, and p65/NF-κB subunit modulates Foxp3 expression, adding new insights in the understanding of the molecular mechanisms involved in regulatory T cell homeostasis and function.
authors.affiliation: Department of Experimental Medicine, Sapienza University, 00161 Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Barbarulo
authors.forename: Paola
authors.initials: P
authors.lastname: Grazioli
authors.forename: Antonio F
authors.initials: AF
authors.lastname: Campese
authors.forename: Diana
authors.initials: D
authors.lastname: Bellavia
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Di Mario
authors.forename: Maria
authors.initials: M
authors.lastname: Pelullo
authors.forename: Ambra
authors.initials: A
authors.lastname: Ciuffetta
authors.forename: Sara
authors.initials: S
authors.lastname: Colantoni
authors.forename: Alessandra
authors.initials: A
authors.lastname: Vacca
authors.forename: Luigi
authors.initials: L
authors.lastname: Frati
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Felli
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D000074121:Protein Kinase C-theta; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007527:Isoenzymes; D016328:NF-kappa B; C499373:Notch3 protein, mouse; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D051996:Transcription Factor RelA; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta