RESUMO
IMP2 (insulin-like growth factor-II mRNA binding protein 2) is an oncofetal protein that is aberrantly expressed in several types of cancer. We recently identified the Imp2 gene as a target gene of the architectural transcription factor HMGA2 (high mobility group A2) and its tumor-specific truncated form HMGA2Tr. In this study, we investigated the mechanism via which HMGA2 regulates Imp2 gene expression. We show that HMGA2 and HMGA2Tr directly regulate transcription of the Imp2 gene by binding to an AT-rich regulatory region located in the first intron. In reporter experiments, we show that this AT-rich regulatory region mimics the response of the endogenous Imp2 gene to HMGA2 and HMGA2Tr. Furthermore, we show that a consensus nuclear factor-kappaB (NF-kappaB) binding site located immediately adjacent to the AT-rich regulatory region binds NF-kappaB and that NF-kappaB and HMGA2 cooperate to regulate Imp2 gene expression. Finally, we provide evidence that there is a strong and statistically significant correlation between HMGA2 and IMP2 gene expression in human liposarcomas.
Assuntos
Proteína HMGA2/fisiologia , Lipossarcoma/metabolismo , NF-kappa B/metabolismo , Proteínas de Ligação a RNA/metabolismo , Sequências Reguladoras de Ácido Nucleico , Transcrição Gênica , Sequência Rica em At , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Sequência de Bases , Sítios de Ligação , Células Cultivadas , Feminino , Proteína HMGA2/genética , Proteína HMGA2/metabolismo , Humanos , Íntrons , Masculino , Camundongos , Pessoa de Meia-Idade , Dados de Sequência Molecular , NF-kappa B/genética , Células NIH 3T3 , Proteínas de Ligação a RNA/genética , Elementos Reguladores de Transcrição , Ativação Transcricional , TransfecçãoRESUMO
The developmentally regulated architectural transcription factor, high mobility group A2 (HMGA2), is involved in growth regulation and plays an important role in embryogenesis and tumorigenesis. Little is known, however, about its downstream targets. We performed a search for genes of which expression is strongly altered during embryonic development in two HMGA2-deficient mouse strains, which display a pygmy-phenotype, as compared to wild-type mice. We found that the insulin-like growth factor II mRNA-binding protein 2 gene (IMP2), but not its family members IMP1 and IMP3, was robustly downregulated in mutant E12.5 embryos. Furthermore, we show that wild-type HMGA2 and its tumor-specific truncated form have opposite effects on IMP2 expression. Our results clearly indicate that HMGA2 differentially regulates expression of IMP family members during embryogenesis.
