The Second AT-hook of the Architectural Transcription Factor HMGA2 is Determinant for Nuclear Localization and Function

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2007 Feb 28

PMID 17324944

Citations 23

Authors

Giacomo Cattaruzzi

Sandro Altamura

Michela A Tessari

Alessandra Rustighi

Vincenzo Giancotti

Carlo Pucillo

Guidalberto Manfioletti

Affiliations

Soon will be listed here.

Abstract

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 beta-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-alpha2 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.

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References

LaCasse E, Lefebvre Y . Nuclear localization signals overlap DNA- or RNA-binding domains in nucleic acid-binding proteins. Nucleic Acids Res. 1995; 23(10):1647-56. PMC: 306917. DOI: 10.1093/nar/23.10.1647. View

Manfioletti G, Giancotti V, Bandiera A, Buratti E, Sautiere P, Cary P . cDNA cloning of the HMGI-C phosphoprotein, a nuclear protein associated with neoplastic and undifferentiated phenotypes. Nucleic Acids Res. 1991; 19(24):6793-7. PMC: 329311. DOI: 10.1093/nar/19.24.6793. View

Huth J, Bewley C, Nissen M, EVANS J, Reeves R, Gronenborn A . The solution structure of an HMG-I(Y)-DNA complex defines a new architectural minor groove binding motif. Nat Struct Biol. 1997; 4(8):657-65. DOI: 10.1038/nsb0897-657. View

Martelli A, Riccio M, Bareggi R, Manfioletti G, Tabellini G, Baldini G . Intranuclear distribution of HMGI/Y proteins. An immunocytochemical study. J Histochem Cytochem. 1998; 46(7):863-4. DOI: 10.1177/002215549804600710. View

Fedele M, Visone R, De Martino I, Troncone G, Palmieri D, Battista S . HMGA2 induces pituitary tumorigenesis by enhancing E2F1 activity. Cancer Cell. 2006; 9(6):459-71. DOI: 10.1016/j.ccr.2006.04.024. View

Thuault S, Valcourt U, Petersen M, Manfioletti G, Heldin C, Moustakas A . Transforming growth factor-beta employs HMGA2 to elicit epithelial-mesenchymal transition. J Cell Biol. 2006; 174(2):175-83. PMC: 2064178. DOI: 10.1083/jcb.200512110. View

Zaidi M, Okada Y, Chada K . Misexpression of full-length HMGA2 induces benign mesenchymal tumors in mice. Cancer Res. 2006; 66(15):7453-9. DOI: 10.1158/0008-5472.CAN-06-0931. View

Narita M, Narita M, Krizhanovsky V, Nunez S, Chicas A, Hearn S . A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation. Cell. 2006; 126(3):503-14. DOI: 10.1016/j.cell.2006.05.052. View

Chiappetta G, Tallini G, De Biasio M, Manfioletti G, Martinez-Tello F, Pentimalli F . Detection of high mobility group I HMGI(Y) protein in the diagnosis of thyroid tumors: HMGI(Y) expression represents a potential diagnostic indicator of carcinoma. Cancer Res. 1998; 58(18):4193-8. View

10.

Sorg G, Stamminger T . Mapping of nuclear localization signals by simultaneous fusion to green fluorescent protein and to beta-galactosidase. Biotechniques. 1999; 26(5):858-62. DOI: 10.2144/99265bm12. View

11.

Nagpal S, Ghosn C, DiSepio D, Molina Y, Sutter M, Klein E . Retinoid-dependent recruitment of a histone H1 displacement activity by retinoic acid receptor. J Biol Chem. 1999; 274(32):22563-8. DOI: 10.1074/jbc.274.32.22563. View

12.

Sgarra R, Tessari M, Di Bernardo J, Rustighi A, Zago P, Liberatori S . Discovering high mobility group A molecular partners in tumour cells. Proteomics. 2005; 5(6):1494-506. DOI: 10.1002/pmic.200401028. View

13.

Fedele M, Pentimalli F, Baldassarre G, Battista S, Klein-Szanto A, Kenyon L . Transgenic mice overexpressing the wild-type form of the HMGA1 gene develop mixed growth hormone/prolactin cell pituitary adenomas and natural killer cell lymphomas. Oncogene. 2005; 24(21):3427-35. DOI: 10.1038/sj.onc.1208501. View

14.

Foti D, Chiefari E, Fedele M, Iuliano R, Brunetti L, Paonessa F . Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice. Nat Med. 2005; 11(7):765-73. DOI: 10.1038/nm1254. View

15.

Fedele M, Fidanza V, Battista S, Pentimalli F, Klein-Szanto A, Visone R . Haploinsufficiency of the Hmga1 gene causes cardiac hypertrophy and myelo-lymphoproliferative disorders in mice. Cancer Res. 2006; 66(5):2536-43. DOI: 10.1158/0008-5472.CAN-05-1889. View

16.

Frasca F, Rustighi A, Malaguarnera R, Altamura S, Vigneri P, Del Sal G . HMGA1 inhibits the function of p53 family members in thyroid cancer cells. Cancer Res. 2006; 66(6):2980-9. DOI: 10.1158/0008-5472.CAN-05-2637. View

17.

Kovac C, Emelyanov A, Singh M, Ashouian N, Birshtein B . BSAP (Pax5)-importin alpha 1 (Rch1) interaction identifies a nuclear localization sequence. J Biol Chem. 2000; 275(22):16752-7. DOI: 10.1074/jbc.M001551200. View

18.

Jans D, Xiao C, Lam M . Nuclear targeting signal recognition: a key control point in nuclear transport?. Bioessays. 2000; 22(6):532-44. DOI: 10.1002/(SICI)1521-1878(200006)22:6<532::AID-BIES6>3.0.CO;2-O. View

19.

Munshi N, Agalioti T, Lomvardas S, Merika M, Chen G, Thanos D . Coordination of a transcriptional switch by HMGI(Y) acetylation. Science. 2001; 293(5532):1133-6. DOI: 10.1126/science.293.5532.1133. View

20.

Fedele M, Battista S, Manfioletti G, Croce C, Giancotti V, Fusco A . Role of the high mobility group A proteins in human lipomas. Carcinogenesis. 2001; 22(10):1583-91. DOI: 10.1093/carcin/22.10.1583. View