title: The SLE-associated Pbx1-d isoform acts as a dominant-negative transcriptional regulator.
abstract: Pbx1 is a transcription factor involved in multiple cellular processes, including the maintenance of self-renewal of hematopoietic progenitors. We have shown that the CD4(+) T-cell expression of a novel splice isoform of Pbx1, Pbx1-d, is associated with lupus susceptibility in the NZM2410 mouse and in lupus patients. The function of Pbx1 in T cells is unknown, but the splicing out of the DNA-binding domain in Pbx1-d predicts a dominant-negative function. In support of this hypothesis, we have shown that Pbx1-d transduction accelerates differentiation of MC3T3-E1 osteoblast pregenitors and mimics the effect of short hairpin RNA silencing of Pbx1. Conversely, Pbx1-d transduction reduced the expression of Sox3, a gene strongly transactivated by Pbx1, and Pbx1-d did not bind the Sox3 promoter. These results constitute a first step towards the understanding on how Pbx1-d contributes to systemic autoimmunity in the NZM2410 mouse model as well as in lupus patients.
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sengupta
authors.forename: S
authors.initials: S
authors.lastname: Liang
authors.forename: H-H S
authors.initials: HH
authors.lastname: Potula
authors.forename: L-J
authors.initials: LJ
authors.lastname: Chang
authors.forename: L
authors.initials: L
authors.lastname: Morel
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation; D004195:Disease Models, Animal; D018398:Homeodomain Proteins / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000276:immunology; D015533:Transcriptional Activation; D014161:Transduction, Genetic
chemical_list: D018398:Homeodomain Proteins; C481797:Pbx1 protein, mouse; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D020033:Protein Isoforms; D055748:SOXB1 Transcription Factors; C527786:Sox3 protein, mouse; D014157:Transcription Factors