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Molecular and Cellular Biology, December 2003, p. 9104-9116, Vol. 23, No. 24
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.24.9104-9116.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Transcriptional Activation of the Cyclin A Gene by the Architectural Transcription Factor HMGA2

Michela A. Tessari,¹ Monica Gostissa,² Sandro Altamura,¹ Riccardo Sgarra,¹ Alessandra Rustighi,³ Clio Salvagno,^1,2 Giuseppina Caretti,⁴ Carol Imbriano,⁴ Roberto Mantovani,^4, Giannino Del Sal,^1,2,5 Vincenzo Giancotti,³ and Guidalberto Manfioletti^1*

Dipartimento di Biochimica, Biofisica e Chimica delle Macromolecole,¹ Centre of Excellence in Biocristallography, University of Trieste, 34127 Trieste,⁵ Laboratorio Nazionale, Consorzio Interuniversitario Biotecnologie, AREA Science Park, 34012 Trieste,² Dipartimento di Patologia e Medicina Sperimentale e Clinica, University of Udine, 33100 Udine,³ Dipartimento di Biologia Animale, University of Modena e Reggio Emilia, 41100 Modena, Italy⁴

Received 5 June 2003/ Returned for modification 15 July 2003/ Accepted 19 September 2003

The HMGA2 protein belongs to the HMGA family of architectural transcription factors, which play an important role in chromatin organization. HMGA proteins are overexpressed in several experimental and human tumors and have been implicated in the process of neoplastic transformation. Hmga2 knockout results in the pygmy phenotype in mice and in a decreased growth rate of embryonic fibroblasts, thus indicating a role for HMGA2 in cell proliferation. Here we show that HMGA2 associates with the E1A-regulated transcriptional repressor p120^E4F, interfering with p120^E4F binding to the cyclin A promoter. Ectopic expression of HMGA2 results in the activation of the cyclin A promoter and induction of the endogenous cyclin A gene. In addition, chromatin immunoprecipitation experiments show that HMGA2 associates with the cyclin A promoter only when the gene is transcriptionally activated. These data identify the cyclin A gene as a cellular target for HMGA2 and, for the first time, suggest a mechanism for HMGA2-dependent cell cycle regulation.

Present address: Dipartimento di Genetica e di Biologia dei Microrganismi, University of Milan, 20133 Milan, Italy.

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