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Differentiation of neuroblastoma cells by phorbol esters and insulin-like growth factor 1 is associated with induction of retinoic acid receptor β gene expression

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Abstract

The retinoic acid (RA) receptor β isoform (RARβ) plays an important role in RA-induced differentiation of human neuroblastoma. In this study we show that insulin-like growth factor 1 (IGF-1) and tetradecanoyl phorbol acetate (TPA) induce RARβ gene expression in neuroblastoma SH-SY5Y cells. IGF-1 and TPA caused a marked induction of RARβ2 promoter activity and had a synergistic effect with RA that also upregulates transcription. The effect of RA is mediated by two RA responsive elements (RAREs), whereas the IGF-1 and TPA actions are independent of the RAREs and map to sequences that overlap the TATA box. These results suggest that the signaling pathways stimulated by TPA and IGF-1 could modify the components assembled at the core RARβ2 promoter and activate transcription. Expression of RasVal12 mimics the effect of IGF-1 and TPA on the promoter, and a dominant negative Ras mutant abrogates activation. A dominant negative Raf also blocks activation showing that the Ras-Raf pathway mediates stimulation of the RARβ2 promoter. Our results show that neuronal differentiation induced by non-retinoid agents that activate Ras is accompanied by increased transcription of the RARβ gene.

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Acknowledgements

We thank H Stunnenberg for constructs containing the RARβ 2 promoter, E Santos for the Ras and Raf vectors, and P Chambon for the receptor antibodies used in this study. We also thank Jorge Martinez de la Mata for his valuable aid. This work has been supported by Grant PM97-0135 from the DGES and 08.1/0032 from the Comunidad de Madrid. G Pérez-Juste is a Fellow from the Comunidad de Madrid.

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  1. Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Arturo Duperier 4, Madrid, 28029, Spain

    German Perez-Juste & Ana Aranda

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  1. German Perez-Juste
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  2. Ana Aranda
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Perez-Juste, G., Aranda, A. Differentiation of neuroblastoma cells by phorbol esters and insulin-like growth factor 1 is associated with induction of retinoic acid receptor β gene expression. Oncogene 18, 5393–5402 (1999). https://doi.org/10.1038/sj.onc.1202906

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