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First published online March 12, 2004
doi: 10.1242/10.1242/jcs.01025
Research Article |
and modulates non-genomic estrogen signaling in breast cancer cells
1 Dipartimento di Genetica, Biologia e Biochimica, Università di Torino, Via Santena 5 bis, 10126 Torino, Italy
2 Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Università del Piemonte Orientale, V.le Ferrucci 33, 28100 Novara, Italy
3 Dipartimento di Scienze Mediche, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
4 Centro Ricerche di Medicina Sperimentale, CeRMS, C. so Bramate 88, 10126 Torino, Italy
Author for correspondence (e-mail: paola.defilippi{at}unito.it)
Accepted 28 November 2003
Steroid hormones bind to their receptors and trans-activate target genes. Rapid non-genomic action of steroid hormones has been proposed in addition to the one at the genomic level. Estrogen has been described to activate c-Src kinase and this activation has been shown to be responsible for estrogen-dependent mitogenicity. A major substrate of c-Src kinase activity is the cytoskeletal protein p130Cas, originally identified in v-Src-transformed cells. We show that in the human breast carcinoma T47D cells, upon estrogen treatment, p130Cas rapidly and transiently associates with the estrogen receptor 
in a multi-molecular complex containing the c-Src kinase and the p85 subunit of PI 3-kinase. Association of p130Cas with the estrogen receptor occurs within 3 minutes of estrogen treatment and is dependent on c-Src kinase activation. Transient overexpression of p130Cas in T47D cells increases estrogen-dependent Src kinase and Erk1/2 MAPKs activities and accelerates their kinetics of stimulation. A similar effect was detected on estrogen-dependent cyclin D1 expression, suggesting a role for p130Cas in regulating estrogen-dependent cell cycle progression. Double-stranded small RNA interference (siRNA) by silencing endogenous p130Cas protein, was sufficient to inhibit estrogen-dependent Erk1/2 MAPKs activity and cyclin D1 induction, demonstrating the requirement of p130Cas in such events. Therefore, our data show that the adaptor protein p130Cas associates with the estrogen receptor transducing complex, regulating estrogen-dependent activation of c-Src kinase and downstream signaling pathways.
Key words: p130Cas, Estrogen, Estrogen receptor, c-Src, Erk1/2 MAPK, Cyclin D1
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