title: Transcriptional regulation of the HMGA1 gene by octamer-binding proteins Oct-1 and Oct-2.
abstract: The High-Mobility Group AT-Hook 1 (HMGA1) protein is an architectural transcription factor that binds to AT-rich sequences in the promoter region of DNA and functions as a specific cofactor for gene activation. Previously, we demonstrated that HMGA1 is a key regulator of the insulin receptor (INSR) gene and an important downstream target of the INSR signaling cascade. Moreover, from a pathogenic point of view, overexpression of HMGA1 has been associated with human cancer, whereas functional variants of the HMGA1 gene have been recently linked to type 2 diabetes mellitus and metabolic syndrome. However, despite of this biological and pathological relevance, the mechanisms that control HMGA1 gene expression remain unknown. In this study, to define the molecular mechanism(s) that regulate HMGA1 gene expression, the HMGA1 gene promoter was investigated by transient transfection of different cell lines, either before or after DNA and siRNA cotransfections. An octamer motif was identified as an important element of transcriptional regulation of this gene, the interaction of which with the octamer transcription factors Oct-1 and Oct-2 is crucial in modulating HMGA1 gene and protein expression. Additionally, we demonstrate that HMGA1 binds its own promoter and contributes to its transactivation by Oct-2 (but not Oct-1), supporting its role in an auto-regulatory circuit. Overall, our results provide insight into the transcriptional regulation of the HMGA1 gene, revealing a differential control exerted by both Oct-1 and Oct-2. Furthermore, they consistently support the hypothesis that a putative defect in Oct-1 and/or Oct-2, by affecting HMGA1 expression, may cause INSR dysfunction, leading to defects of the INSR signaling pathway.
authors.affiliation: Department of Health Sciences, University "Magna Græcia" of Catanzaro, Viale Europa (Loc. Germaneto), Catanzaro, Italy.
authors.forename: Eusebio
authors.initials: E
authors.lastname: Chiefari
authors.affiliation: Department of Health Sciences, University "Magna Græcia" of Catanzaro, Viale Europa (Loc. Germaneto), Catanzaro, Italy.
authors.forename: Biagio
authors.initials: B
authors.lastname: Arcidiacono
authors.affiliation: Department of Health Sciences, University "Magna Græcia" of Catanzaro, Viale Europa (Loc. Germaneto), Catanzaro, Italy.
authors.forename: Katiuscia
authors.initials: K
authors.lastname: Possidente
authors.affiliation: Department of Health Sciences, University "Magna Græcia" of Catanzaro, Viale Europa (Loc. Germaneto), Catanzaro, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Iiritano
authors.affiliation: Department of Health Sciences, University "Magna Græcia" of Catanzaro, Viale Europa (Loc. Germaneto), Catanzaro, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Ventura
authors.affiliation: Department of Health Sciences, University "Magna Græcia" of Catanzaro, Viale Europa (Loc. Germaneto), Catanzaro, Italy.
authors.forename: Rosantony
authors.initials: R
authors.lastname: Pandolfo
authors.affiliation: Department of Medical and Surgical Sciences, University "Magna Græcia" of Catanzaro, Viale Europa (Loc. Germaneto), Catanzaro, Italy.
authors.forename: Francesco Saverio
authors.initials: FS
authors.lastname: Brunetti
authors.affiliation: Department of Experimental and Clinical Medicine, University "Magna Græcia" of Catanzaro, Viale Europa (Loc. Germaneto), Catanzaro, Italy.
authors.forename: Manfredi
authors.initials: M
authors.lastname: Greco
authors.affiliation: Department of Health Sciences, University "Magna Græcia" of Catanzaro, Viale Europa (Loc. Germaneto), Catanzaro, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Foti
authors.affiliation: Department of Health Sciences, University "Magna Græcia" of Catanzaro, Viale Europa (Loc. Germaneto), Catanzaro, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Brunetti
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism; D005786:Gene Expression Regulation; D025741:HMGA1a Protein / Q000235:genetics*; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D059372:Nucleotide Motifs; D050811:Octamer Transcription Factor-1 / Q000378:metabolism*; D050813:Octamer Transcription Factor-2 / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011972:Receptor, Insulin / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D050811:Octamer Transcription Factor-1; D050813:Octamer Transcription Factor-2; C494165:POU2F1 protein, human; C058435:POU2F2 protein, human; D025741:HMGA1a Protein; D011972:Receptor, Insulin