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ABSTRACT: An appropriate concentration of intracellular T(3) is a critical determinant of placenta development and function and is mainly controlled by the activity of type II deiodinase (D2). The levels of this enzyme are finely regulated in different tissues by coordinated transcriptional mechanisms, which rely on dedicated promoter sequences (e.g. cAMP response element and TATA elements) that impart inducibility and tissue specificity to Dio2 mRNA expression. Here we show that CCAAT enhancer-binding proteins α and β (C/EBPα and C/EBPβ) promote Dio2 expression in the trophoblastic cell line JEG3 through a conserved CCAAT element, which is a novel key component of the Dio2 promoter code that confers tissue-specific expression of D2 in these cells. Increased C/EBPs levels potently induce Dio2 transcription, whereas their ablation results in loss of Dio2 mRNA. By measuring the activity of several deletion and point mutant promoter constructs, we have identified the functional CCAAT element responsible for this effect, which is located in close proximity to the most 5' TATA box. Notably, this newly identified sequence is highly conserved throughout the species and binds in vivo and in vitro C/EBP, indicating the relevance of this regulatory mechanism. Together, our results unveil a novel mechanism of regulation of D2 expression in a trophoblastic cell line, which may play a relevant role during placenta development.
Endocrinology 06/2012; 153(8):4030-8. · 4.46 Impact Factor
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Gianluca Canettieri,
Lucia Di Marcotullio,
Azzura Greco,
Sonia Coni, Laura Antonucci,
Paola Infante,
Laura Pietrosanti,
Enrico De Smaele,
Elisabetta Ferretti,
Evelina Miele, [......],
Giuseppina De Simone,
Emilia Maria Pedone,
Paola Gallinari,
Alessandra Giorgi,
Christian Steinkühler,
Luigi Vitagliano,
Carlo Pedone,
M Eugenià Schinin,
Isabella Screpanti,
Alberto Gulino
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ABSTRACT: Hedgehog signalling is crucial for development and is deregulated in several tumours, including medulloblastoma. Regulation of the transcriptional activity of Gli (glioma-associated oncogene) proteins, effectors of the Hedgehog pathway, is poorly understood. We show here that Gli1 and Gli2 are acetylated proteins and that their HDAC-mediated deacetylation promotes transcriptional activation and sustains a positive autoregulatory loop through Hedgehog-induced upregulation of HDAC1. This mechanism is turned off by HDAC1 degradation through an E3 ubiquitin ligase complex formed by Cullin3 and REN, a Gli antagonist lost in human medulloblastoma. Whereas high HDAC1 and low REN expression in neural progenitors and medulloblastomas correlates with active Hedgehog signalling, loss of HDAC activity suppresses Hedgehog-dependent growth of neural progenitors and tumour cells. Consistent with this, abrogation of Gli1 acetylation enhances cellular proliferation and transformation. These data identify an integrated HDAC- and ubiquitin-mediated circuitry, where acetylation of Gli proteins functions as an unexpected key transcriptional checkpoint of Hedgehog signalling.
Nature Cell Biology 02/2010; 12(2):132-42. · 19.49 Impact Factor
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Cell cycle (Georgetown, Tex.) 05/2009; 8(7):963-4. · 5.36 Impact Factor
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ABSTRACT: Regulation of gene expression in response to mitogenic stimuli is a critical aspect underlying many forms of human cancers. The AP-1 complex mediates the transcriptional response to mitogens, and its deregulation causes developmental defects and tumors. We report that the coactivator CRTC1 cyclic AMP response element-binding protein (CREB)-regulated transcription coactivator 1 is a potent and indispensable modulator of AP-1 function. After exposure of cells to the AP-1 agonist 12-O-tetradecanoylphorbol-13-acetate (TPA), CRTC1 is recruited to AP-1 target gene promoters and associates with c-Jun and c-Fos to activate transcription. CRTC1 consistently synergizes with the proto-oncogene c-Jun to promote cellular growth, whereas AP-1-dependent proliferation is abrogated in CRTC1-deficient cells. Remarkably, we demonstrate that CRTC1-Maml2 oncoprotein, which causes mucoepidermoid carcinomas, binds and activates both c-Jun and c-Fos. Consequently, ablation of AP-1 function disrupts the cellular transformation and proliferation mediated by this oncogene. Together, these data illustrate a novel mechanism required to couple mitogenic signals to the AP-1 gene regulatory program.
Proceedings of the National Academy of Sciences 02/2009; 106(5):1445-50. · 9.68 Impact Factor
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Gianluca Canettieri,
Lucia Di Marcotullio,
Azzura Greco,
Sonia Coni, Laura Antonucci,
Paola Infante,
Laura Pietrosanti,
Enrico De Smaele,
Elisabetta Ferretti,
Evelina Miele, [......],
Giuseppina De Simone,
Emilia Maria Pedone,
Paola Gallinari,
Alessandra Giorgi,
Christian Steinükhler,
Luigi Vitagliano,
Carlo Pedone,
M. Eugenia Schinin,
Isabella Screpanti,
Alberto Gulino
