title: The HMGA1 protoncogene frequently deregulated in cancer is a transcriptional target of E2F1.
abstract: Reactivation of the HMGA1 protoncogene is very frequent in human cancer, but still very little is known on the molecular mechanisms leading to this event. Prompted by the finding of putative E2F binding sites in the human HMGA1 promoter and by the frequent deregulation of the RB/E2F1 pathway in human carcinogenesis, we investigated whether E2F1 might contribute to the regulation of HMGA1 gene expression. Here we report that E2F1 induces HMGA1 by interacting with a 193 bp region of the HMGA1 promoter containing an E2F binding site surrounded by three putative Sp1 binding sites. Both gain and loss of function experiments indicate that Sp1 functionally interacts with E2F1 to promote HMGA1 expression. However, while Sp1 constitutively binds HMGA1 promoter, it is the balance between different E2F family members that tunes the levels of HMGA1 expression between quiescence and proliferation. Finally, we found increased HMGA1 expression in pituitary and thyroid tumors developed in Rb(+/-) mice, supporting the hypothesis that E2F1 is a novel important regulator of HMGA1 expression and that deregulation of the RB/E2F1 path might significantly contribute to HMGA1 deregulation in cancer.
authors.affiliation: Department of Experimental Medicine, Sapienza University, Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Massimi
authors.forename: Francesca
authors.initials: F
authors.lastname: Guerrieri
authors.forename: Marialaura
authors.initials: M
authors.lastname: Petroni
authors.forename: Veronica
authors.initials: V
authors.lastname: Veschi
authors.forename: Silvia
authors.initials: S
authors.lastname: Truffa
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
authors.forename: Luigi
authors.initials: L
authors.lastname: Frati
authors.forename: Massimo
authors.initials: M
authors.lastname: Levrero
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D025741:HMGA1a Protein / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D010911:Pituitary Neoplasms / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D016160:Retinoblastoma Protein / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D050687:E2F1 Transcription Factor; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D016329:Sp1 Transcription Factor; D025741:HMGA1a Protein