Nucleic Acids Research Advance Access published online on February 25, 2007
Nucleic Acids Research, doi:10.1093/nar/gkl1106
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Molecular Biology |
The second AT-hook of the architectural transcription factor HMGA2 is determinant for nuclear localization and function
1Dipartimento di Scienze e Tecnologie Biomediche, University of Udine, P.le Kolbe, 4 - 33100 Udine, Italy 2Dipartimento di Biochimica, Biofisica e Chimica delle Macromolecole, University of Trieste, via Giorgieri, 1 - 34127 Trieste, Italy 3Present address: BioFocus DPI, Archimedesweg 4, P.O. Box 2048, 2301CA Leiden, The Netherlands 4Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie, AREA Science Park, 34012 Trieste, Italy
*To whom correspondence should be addressed. Tel: +39 040 5583675; Fax: +39 040 5583694; Email: manfiole{at}units.it
Received September 27, 2006. Revised December 1, 2006. Accepted December 4, 2006.
High Mobility Group A (HMGA) is a family of architectural nuclear factors which play an important role in neoplastic transformation. HMGA proteins are multifunctional factors that associate both with DNA and nuclear proteins that have been involved in several nuclear processes including transcription. HMGA localization is exclusively nuclear but, to date, the mechanism of nuclear import for these proteins remains unknown. Here, we report the identification and characterization of a nuclear localization signal (NLS) for HMGA2, a member of the HMGA family. The NLS overlaps with the second of the three AT-hooks, the DNA-binding domains characteristic for this group of proteins. The functionality of this NLS was demonstrated by its ability to target a heterologous ß-galactosidase/green fluorescent protein fusion protein to the nucleus. Mutations to alanine of basic residues within the second AT-hook resulted in inhibition of HMGA2 nuclear localization and impairment of its function in activating the cyclin A promoter. In addition, HMGA2 was shown to directly interact with the nuclear import receptor importin-
2 via the second AT-hook. HMGA proteins are overexpressed and rearranged in a variety of tumors; our findings can thus help elucidating their role in neoplastic transformation.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.