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Vol. 20, Issue 14, 3353-3362, July 15, 2009

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Induction of Dlk1 by PTTG1 Inhibits Adipocyte Differentiation and Correlates with Malignant Transformation

Águeda G. Espina^*,, Cristina Méndez-Vidal^*,, Miguel A. Moreno-Mateos^*,, Carmen Sáez, Ana Romero-Franco^*, Miguel A. Japón, and José A. Pintor-Toro^*

*Centro Andaluz de Biología Molecular y Medicina Regenerativa, CABIMER-CSIC, 41092 Sevilla, Spain; and Departamento de Anatomía Patológica, Hospital Universitario Virgen del Rocío, 41013 Sevilla, Spain

Submitted September 23, 2008; Revised April 16, 2009; Accepted May 18, 2009
Monitoring Editor: John L. Cleveland

Pituitary tumor-transforming gene-1 (PTTG1) is an oncogene highly expressed in a variety of endocrine, as well as nonendocrine-related cancers. Several tumorigenic mechanisms for PTTG1 have been proposed, one of the best characterized being its capacity to act as a transcriptional activator. To identify novel downstream target genes, we have established cell lines with inducible expression of PTTG1 and a differential display approach to analyze gene expression changes after PTTG1 induction. We identified dlk1 (also known as pref-1) as one of the most abundantly expressed PTTG1 targets. Dlk1 is known to participate in several differentiation processes, including adipogenesis, adrenal gland development, and wound healing. Dlk1 is also highly expressed in neuroendocrine tumors. Here, we show that PTTG1 overexpression inhibits adipogenesis in 3T3-L1 cells and that this effect is accomplished by promoting the stability and accumulation of Dlk1 mRNA, supporting a role for PTTG1 in posttranscriptional regulation. Moreover, both pttg1 and dlk1 genes show concomitant expression in fetal liver and placenta, as well as in pituitary adenomas, breast adenocarcinomas, and neuroblastomas, suggesting that PTTG1 and DLK1 are involved in cell differentiation and transformation.

These authors contributed equally to this work.

Address correspondence to: José A. Pintor-Toro (jose.pintor{at}cabimer.es)

Abbreviations used: csd, stearoyl-CoA desaturase; IPTG, isopropylthiogalactoside; pttg1, pituitary tumour-transforming gene.