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Transcriptional activation of the cyclin A gene by the architectural transcription factor HMGA2.

ABSTRACT: 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.

SUBMITTER: Tessari MA

PROVIDER: S-EPMC309667 | biostudies-other | 2003 Dec

REPOSITORIES: biostudies-other

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The second AT-hook of the architectural transcription factor HMGA2 is determinant for nuclear localization and function.

Project description: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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Correction: HMGA2, the architectural transcription factor high mobility group, is expressed in the developing and mature mouse cochlea.

Project description:[This corrects the article DOI: 10.1371/journal.pone.0088757.].

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Transcription profiling of parotid glands from mice with targeted expression of architectural transcription factor HMGA2

Project description:Targeted expression of architectural transcription factor HMGA2 in salivary glands of transgenic mice.

2007-01-01 | E-MEXP-871 | biostudies-arrayexpress

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Regulation of the cyclin E gene by transcription factor E2F1.

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The transcription factor ATF3 is upregulated during chondrocyte differentiation and represses cyclin D1 and A gene transcription.

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Transcriptional activation by mitochondrial transcription factor A involves preferential distortion of promoter DNA.

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Transfusion independence and HMGA2 activation after gene therapy of human ?-thalassaemia.

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