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J. Biol. Chem., Vol. 278, Issue 34, 31737-31744, August 22, 2003

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Estrogen Receptor , a Molecular Switch Converting Transforming Growth Factor--mediated Proliferation into Differentiation in Neuroblastoma Cells^*

Paolo Ciana, Serena Ghisletti, Paola Mussi, Ivano Eberini , Elisabetta Vegeto and Adriana Maggi 

From the Center of Excellence on Neurodegenerative Diseases and Center of Biotechnology and Pharmacology, University of Milan, 20133 Milan, Italy and Proteomics and Protein Structure Study Group, Department of Pharmacological Sciences, University of Milan, 20133 Milan, Italy

Transforming growth factor- (TGF-) is known to promote both proliferation and differentiation of neural cell progenitors. Using the human neuroblastoma cell line SK-N-BE that is induced to proliferate by TGF-, we demonstrated that the expression of a single transcription factor, the estrogen receptor- (ER), can reroute the TGF- mitogenic signaling toward a path leading to differentiation. With selected mutations in ER and signal transducer and activator of transcription 3 (Stat3), we demonstrated that the blockade of TGF- mitotic potential was not dependent on ER DNA binding activity but required a transcriptionally active Stat3. In neuroblastoma cells, 17-estradiol treatment induced a transient increase in the transcription of estrogen-responsive element-containing promoters including those regulating TGF- and prothymosin synthesis. Based on the data presented, we hypothesized that in the presence of prothymosin , ER activates its direct target genes and increases cell proliferation, whereas in the presence of high levels of TGF-, ER preferentially interacts with Stat3 and causes cell differentiation. Our results reveal a novel form of "end-product" regulation of an intracellular receptor that occurs through recruitment of membrane receptors and their signaling effector system. Cross-coupling between membrane and intracellular receptors has been described by several laboratories. This study proves the relevance of these interactions in cellular responses to growth factors.

Received for publication, February 12, 2003 , and in revised form, April 16, 2003.

^* This research was supported by Associazione Italiana per la Ricerca sul Cancro, Ministero dell'Universita e della Ricerca Scientifica e Tecnologica Grant MM06262191, Consiglio Nazionale delle Richerche Target Project, Cariplo, European Union Project Grant QLRT-2001-02221, and Telthon Grant GGP02336. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Center of Excellence on Neurodegenerative Diseases, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. Tel.: 39-02-50318375; Fax: 39-02-50318290/39-02-50318284; E-mail: adriana.maggi{at}unimi.it.

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