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Grg1 Acts as a Lung-Specific Oncogene in a Transgenic Mouse Model

¹ Molecular and Cellular Biology Division, Sunnybrook and Women's College Health Science Centre; ² Toronto-Sunnybrook Regional Cancer Centre; Departments of ³ Medical Biophysics, ⁴ Laboratory Medicine and Pathobiology, and ⁵ Physiology, University of Toronto; ⁶ Lung Biology Research Program, Hospital for Sick Children Research Institute; ⁷ Ontario Cancer Institute, University Health Network-Princess Margaret Hospital; and ⁸ St. Michael's Hospital, Toronto, Ontario, Canada

Requests for reprints: Corrinne G. Lobe, Molecular and Cellular Biology Division, Sunnybrook and Women's College Health Science Centre, S-236, 2075 Bayview Avenue, Toronto, ON, Canada M4N 3M5. Phone: 416-480-6100, ext. 3382; Fax: 416-480-5703; E-mail: corrinne.lobe{at}swri.on.ca.

Groucho proteins are transcriptional corepressors that are recruited to gene regulatory regions by numerous transcription factors. Long isoforms, such as Grg1, have all the domains of the prototype Drosophila Groucho. Short Groucho proteins, such as Grg5, have only the amino-terminal Q and G/P domains. We generated Grg1 and Grg5 transgenic mice and found that Grg1 overexpression induces lung adenocarcinoma, whereas Grg5 overexpression does not. Coexpression of Grg5 with Grg1 reduces tumor burden. Grg1 and Grg5 both diminish p53 protein levels; however, only Grg1 overexpression induces elevated levels of ErbB1 and ErbB2 receptor tyrosine kinases. The molecular and biological changes that accompany tumor progression in Grg1 transgenic mice closely reiterate events seen in human lung cancer. We also found that within a human lung tumor tissue array, a significant number of carcinomas overexpress Grg1/TLE1. Our data suggest that Grg1 overexpression contributes to malignancy in human lung cancers. (Cancer Res 2006; 66(3): 1294-301)

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