Differential regulation of the insulin‐like growth factor II mRNA‐binding protein genes by architectural transcription factor HMGA2

Abstract

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 pygmyphenotype, 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.

HMGA2 Regulates Transcription of the Imp2 Gene via an Intronic Regulatory Element in Cooperation with Nuclear Factor-κB

“…More important, however, HMGA2 overexpression enhanced luciferase expression from reporter plasmid B almost 2-fold, whereas HMGA2Tr strongly repressed the activity of the same reporter. This latter result reflects the endogenous Imp2 mRNA expression changes induced by HMGA2 and HMGA2Tr, as seen previously in Northern blot analyses (10). Furthermore, measuring the effect of HMGA2 and HMGA2Tr on reporter gene expression via combination of region A and B, where A is functioning as a promoter and B as an enhancer, gave a similar result.…”

“…A first major finding is the identification of an AT-rich regulatory region in the first intron of the Imp2 gene. In reporter experiments, this AT-rich region mimics the response of the endogenous Imp2 gene to the architectural transcription factor HMGA2 and its truncated tumor-specific counterpart HMGA2Tr, as shown by Brants et al (10). In addition, we show that the HMGA2 protein binds directly to the AT-rich region and is also associated with this (33).…”

“…Previous work from our group identified Imp2 as a target gene of both wild-type and tumor-specific truncated HMGA2 proteins, suggesting an HMGA2-dependent Imp2 expression regulation that plays an important role during embryonic development and in tumorigenesis (10). In this study, we investigated the mechanism via which HMGA2 regulates Imp2 gene expression.…”

“…Previous work from our group identified Imp2 as a target gene of both wild-type and tumor-specific truncated HMGA2 proteins (10). HMGA2 and HMGA2Tr contain three DNAbinding domains, called AT-hooks, enabling their binding to AT-rich DNA.…”

“…IMP1, IMP2, and IMP3 are each encoded by a separate gene, and previous work from our group clearly indicates that the mRNA level of Imp2, but not of Imp1 and Imp3, is developmentally regulated by the architectural transcription factor HMGA2 (high mobility group A2; ref. 10). Like IMP2, HMGA2 is an oncofetal protein: it is expressed at high levels during embryonic development (11,12), whereas it is hardly detectable in adult tissues (13).…”